In 2006, Higgins wrote new material for her second album, and following a US tour she recorded On a Clear Night, which gave her another No. 1 single with "Steer". Higgins has conducted several well received Australian tours and performed at high-profile charity events WaveAid (2005) and Live Earth (2007). She has toured internationally and lived and worked in the United States for ten months in 2008. Her song "Where I Stood" has been used in television shows including Grey's Anatomy, One Tree Hill and So You Think You Can Dance. Alongside her music career, Higgins pursues interests in animal rights and the environment, endeavouring to make her tours carbon neutral. She is also the patron of One in Five, an Australian mental health charity. In 2007, following years of press speculation about her sexual orientation, she came out as bisexual, saying that she prefers interviewers to focus on her music. In 2010 she made her acting debut in feature Bran Nue Dae, and performed on the related soundtrack.

Melissa "Missy" Morrison Higgins was born 19 August 1983 in Melbourne, Victoria to Christopher Higgins, an English-Australian general practitioner, and Margaret (née Morrison), an Australian childcare centre operator. Her sister, Nicola is seven years older, and brother, David is six years older. She learned to play classical piano from age six, following in the footsteps of Christopher and David, but realised she wanted to be a singer at about 12 when she appeared in an Armadale Primary School production of Andrew Lloyd Webber's musical Joseph and the Amazing Technicolor Dreamcoat. Bored with practice, she gave up playing piano at that time. Hoping for more freedom, she urged her parents to send her to Geelong Grammar School, an independent boarding school attended by her siblings. At Geelong she took up the piano again, this time playing jazz including performing with David's group on weekends. She was introverted and found that piano practice helped her cope with living at boarding school.

At 15, she wrote "All for Believing" for a school music assignment and completed it just hours before the deadline. The assignment earned an A and she performed her song in front of classmates. She approached a Melbourne record company and was told that they wanted more than one song. She wrote more songs and worked with the Kool Skools project, which enables students to record music. In 2001, Nicola entered "All for Believing" on Higgins' behalf into Unearthed, radio station Triple J's competition for unsigned artists. The song won the competition and was added to the station's play list. Two record companies showed an interest in Higgins—Sony and Eleven. She signed with Eleven, partly because they agreed that she would not be "made into a pop star" and partly because they were happy for her to take time off for backpacking. Her manager is Eleven's John Watson, who also manages rock band Silverchair. He later said "Missy's the only time in my career I knew after 90 seconds I really wanted to sign her." The backpacking trip had been planned with a friend for years and they spent most of 2002 in Europe; while she was travelling, "All for Believing" started to be played by Los Angeles radio station KCRW. This brought attention from US record labels and, by year's end, an international recording deal with Warner Bros.

Higgins was the support act on a 2003 Australian tour by folk rock band The Waifs and rock band george. She travelled to the US to work with producer, John Porter, and recorded her first extended play (EP) entitled Missy Higgins, which was released in November and entered the Australian Recording Industry Association (ARIA) Singles Chart Top 50 in August 2004.

She toured Australia, supporting both Pete Murray and The John Butler Trio. Her second four-track EP Scar was released in July. The title track "Scar", co-written with US songwriter, Kevin Griffin, debuted at No. 1 on the ARIA Charts. Her first album, The Sound of White, was released in September, and debuted at No. 1 on the ARIA Albums Chart. Also produced by Porter, it sold over 500,000 copies. She was nominated in five categories at the ARIA Music Awards of 2004 for "Scar": Best Female Artist', 'Single of the Year', 'Best Pop Release', 'Breakthrough Artist – Single' and 'Best Video' (directed by Squareyed Films). At the awards ceremony on 17 October she received the award for Best Pop Release, beating Delta Goodrem, The Dissociatives, Kylie Minogue and Pete Murray. This was followed by her first national headline tour. Her second single "Ten Days" was co-written with Jay Clifford (guitarist in US band Jump, Little Children) and was inspired by Higgins' 2002 break-up with her boyfriend before she travelled to Europe. Released in November, it peaked at No. 12.

On 29 January 2005 Higgins performed with other local musicians including Nick Cave and Powderfinger at the WaveAid fundraising concert in the Sydney Cricket Ground. The concert raised AUS$2.3 million for four charities supporting the victims of the 2004 Indian Ocean earthquake. In March Higgins performed at the MTV Australia Awards and won the prize for 'Breakthrough Artist of the Year'. The following month she released her third single, "The Special Two", which was a radio hit and reached No. 2. "The Special Two" was released on an EP which included her cover of the Skyhooks song, "You Just Like Me Cos I'm Good In Bed", recorded for Triple J's 30th anniversary. The song had been the first track played on Triple J when it launched (as Double J) in 1975. In May, Higgins won the 'Song of the Year' and 'Breakthrough' awards for "Scar" from the Australasian Performing Right Association (APRA). She continued touring in mid-2005 and released her fourth single, "The Sound of White", in August. In September she played a sold out performance at the Vanguard in Sydney with the proceeds going to One in Five, her sponsored mental health charity. She was nominated for seven more ARIAs and in October won 'Album of the Year', 'Best Pop Release', 'Breakthrough Artist – Album' and 'Highest Selling Album' (all for The Sound of White) and 'Best Female Artist' (for "Scar"). She teamed up with fellow ARIA award-winning singer Ben Lee in late 2005 for a national tour.

During 2006, Higgins lived in Broome, Western Australia for six months, away from the entertainment industry. The relaxed lifestyle helped her focus on writing new material. The landscape made a big impression, "It was the first place I'd ever felt honestly connected with my country, with the physical land of my country" and inspired her to write "Going North". She then toured the United States and South Africa, writing more material on the road. In September she based herself in Los Angeles to record her second album, On a Clear Night, with producer Mitchell Froom. "Steer" was released as an EP, followed a fortnight later by its album on 28 April 2007, both debuted at No. 1 on their respective charts.

In February, Higgins had contributed a tribute song to the album, Cannot Buy My Soul, for noted indigenous singer, Kev Carmody, singing "Droving Woman" with musician Paul Kelly and group Augie March. On 7 July, she participated in the Live Earth concert in Sydney, performing her own set before joining Carmody, Kelly and vocalist John Butler on stage for the song "From Little Things Big Things Grow". Emily Dunn in The Sydney Morning Herald wrote "[the song] could have been the event's anthem". Rolling Stone's Dan Lander pointed out a highlight, when the "whole crowd sung along – all eleven verses."

Higgins returned to Los Angeles to focus on the US market—she spent September and October touring—where she was still relatively unknown. On 26 October, backed by the Sydney Youth Orchestra, she headlined the annual Legs 11 concert, a breast cancer benefit held in The Domain, Royal Botanic Gardens, Sydney. Two days later Higgins performed at the 2007 ARIAs where she was nominated for 'Best Pop Release', 'Highest Selling Album' and 'Highest Selling Single' (for "Steer") and won 'Best Female Artist' (for On a Clear Night)—her seventh ARIA Music Award. On 31 October, she was a guest at television music channel MAX's inaugural Concert for the Cure, a private concert for people affected by breast cancer. She sang headline act Powderfinger's "Sunsets" with front man Bernard Fanning and joined in with the encore of "These Days". She spent November and December on her For One Night Only Tour, taking in Cairns, Sydney and Perth. You Am I lead singer, Tim Rogers, joined her on some shows.

On a Clear Night, was released in the US on 26 February 2008, supported by a tour in March. Her ten-month stay in Los Angeles during 2008 promoted her songs for films and television shows. Her first US single "Where I Stood" was featured in US series including Grey's Anatomy, One Tree Hill and So You Think You Can Dance. During 2008, Higgins supported the Indigo Girls and then Ben Folds on their respective US tours. February and March 2009 saw her co-headlining a US tour with Canadian Justin Nozuka. On 31 March she released an EP, More Than This in Australia featuring cover versions of "More Than This" by Roxy Music, "(I'm) In Love Again" by Peggy Lee, "Breakdown" by Tom Petty and "Moses" by Patty Griffin. "Moses" had been included on Triple J's 2005 compilation album Like a Version: Volume One and "More Than This" was recorded as part of Covered, A Revolution in Sound, a Warner Bros. tribute album also released in March 2009.