A 2013 Guggenheim Fellow, Melford was described by the San Francisco Chronicle as an "explosive player, a virtuoso who shocks and soothes, and who can make the piano stand up and do things it doesn't seem to have been designed for.

[4][5] Pushed towards performing classical repertoire, Melford attended a Northwestern University extension program in junior high school.

[5]While living in Olympia, Melford met prominent avant-garde musicians including Oliver Lake, Anthony Braxton, Marty Ehrlich and Leroy Jenkins, whose performance with Amina Claudine Myers and Pheeroan akLaff inspired an "ecstatic feeling" which intensified her commitment to improvisation.

In the late 1980s she played and recorded with flutist Marion Brandis, and formed a trio with bassist Lindsey Horner and drummer Reggie Nicholson.

She also formed a second five-piece, the Same River, Twice, featuring Douglas, cellist Erik Friedlander, reed player Chris Speed, and drummer Michael Sarin.

"[11] In 2000, Melford formed Crush, a trio in which she played piano and harmonium with Kenny Wollesen on drums and Stomu Takeishi on electric bass.

Although it remained unreleased until 2006, Be Bread's debut album, The Image of Your Body (whose title was derived from a Rumi poem), was recorded in 2003, as was Where the Two Worlds Touch by Myra Melford's The Tent, released by Arabesque.

In 2006, along with bassist Mark Dresser and drummer Matt Wilson, Melford formed Trio M, who released their debut album, The Big Picture, on Cryptogramophone in 2007.

[13] Melford formed a new quintet, Snowy Egret, featuring bassist Takeishi, guitarist Liberty Ellman, trumpeter Ron Miles, and drummer Tyshawn Sorey in 2012.

That same year, she was named a Guggenheim Fellow and received both the Doris Duke Charitable Foundation's Performing Artist Award and a Doris Duke Residency to Build Demand for the Arts for her efforts to re-imagine the jazz program at San Francisco's Yerba Buena Center for the Arts;[12][15] in November, Snowy Egret performed the music for Melford's multimedia project Language of Dreams, at the center.