Biss made his New York recital debut in 2000 at the 92nd Street Y. In early 2001, he performed with the New York Philharmonic under the baton of Kurt Masur. His European career was launched in 2002 when he became the first American to be selected as a BBC New Generation Artist, winning a Borletti-Buitoni Trust Award the following year. He made his recital debut at Carnegie Hall in January 2011.

In 2010, Biss was appointed to the piano faculty as Neubauer Family Chair at his alma mater the Curtis Institute of Music. As part of his teaching career, Jonathan Biss became the first classical musician to partner with Coursera. Together they created Exploring Beethoven’s Piano Sonatas, a free video course on several of Beethoven’s most famous sonatas. The course has reached more than 150,000 students in more than 185 countries. He will continue to add lectures until he covers all the sonatas.

Biss was born into a family of musicians in Bloomington, Indiana. His paternal step-grandmother was one of the first well-known female cellists, the Russian cellist Raya Garbousova, for whom Samuel Barber wrote his cello concerto. His parents, Miriam Fried and Paul Biss, are both violinists. After studying at Indiana University, where both of his parents taught, Biss entered the Curtis Institute of Music at the age of 17 to study with Leon Fleisher. Interviewed by The New York Times in 2011 in the run-up to Biss’ Carnegie Hall debut recital, Leon Fleisher said of his pupil:

Throughout his career, Biss has been particularly noted for his immersive focus on single composers. In 2011, on Beethoven’s birthday, he released the eBook Beethoven’s Shadow, a 19,000 word meditation on the art of performing Beethoven’s piano sonatas. Biss was the first classical musician to be commissioned to write a Kindle eBook. Shortly after, in January 2012, the record label Onyx released the first of Jonathan Biss’ recordings of the complete Beethoven Sonatas. The disc was the first in a series of nine discs to be released over as many years. To date, eight albums have been recorded and the ninth will be released in November 2019. Biss dedicated his 2012-2013 season to Robert Schumann, declaring himself to be “a fanatic for every note Schumann wrote.” The project was entitled “Schumann: Under the Influence” and explored Schumann’s influences and his legacy. Biss performed a series of concerts internationally with pieces by Schumann’s predecessors such as Mozart, Beethoven, and Purcell, and composers who have been influenced by his music such as Leoš Janáček, Alban Berg and contemporary composers György Kurtág and Timo Andres. As part of the project, Biss wrote a Kindle Single eBook entitled A Pianist Under the Influence. The work explained Biss’s lifelong, intense, multi-layered relationship with the composer’s music and was excerpted on Slate. Biss also released an album of Schumann and Dvořák with Elias String Quartet.

Biss is also an advocate for new music. He has commissioned pieces including Lunaire Variations by David Ludwig, Interlude II by Leon Kirchner, Wonderer by Lewis Spratlan, and Three Pieces for Piano and a concerto by Bernard Rands, which he premiered with the Boston Symphony Orchestra. He has also premiered a piano quintet by William Bolcom. In 2016 Biss launched Beethoven/5, for which the Saint Paul Chamber Orchestra is commissioning five composers to write new piano concertos, each inspired by one of Beethoven’s five piano concertos. Biss has already premiered “The Blind Banister” by Timo Andres, which was named a Finalist for the Pulitzer Prize for Music, “City Stanzas” by Sally Beamish, “Il sogno di Stradella” by Salvatore Sciarrino and “Watermark” by Caroline Shaw. In 2020 he will premiere “Gneixendorfer Musik – eine Winterreise” by Brett Dean.

Biss has begun examining, both in concert and academically, the concept of a composer’s “late style,” focusing on musicians who went in surprising directions towards the end of their lives. He has put together several programs of Bach, Beethoven, Brahms, Britten, Elgar, Gesualdo, Kurtág, Mozart, Schubert, and Schumann’s later works, which he performed with the Brentano Quartet and Mark Padmore in the UK, Italy, the Netherlands, and across the United States. He also gave masterclasses at Carnegie Hall in connection with the idea of late style and published Coda, a Kindle single on the topic in March 2017.

On August 6, 2018 Marlboro Music announced that Biss would assume the role of co-artistic director (with Mitsuko Uchida) of the Marlboro Music Festival in Vermont. Biss has a long connection with Marlboro where he spent 12 summers as both a junior and senior participant.

Starting in September 2019, in the lead-up to the 250th anniversary of Beethoven’s birth in December 2020, Biss will perform a whole season focused around Beethoven’s Piano Sonatas, with more than 50 recitals worldwide. This includes performing the complete sonatas at the Wigmore Hall and Berkeley, multi-concert-series in Washington, Philadelphia and Seattle, as well as recitals in Rome, Budapest, New York and Sydney.