Kalfus started college at Sarah Lawrence College, Bronxville, but dropped out after the first year. Kalfus later attended the New School for Social Research in Manhattan and New York University. Kalfus started writing at an early age.
Kalfus began his career by publishing short stories and now writes novels. His most recent novel was Equilateral (2013). His previous novel, A Disorder Peculiar to the Country (2006), was a National Book Award nominee. His first novel was The Commissariat of Enlightenment (2003), preceded by short story collections PU-239 and Other Russian Fantasies (1999) and Thirst (1998). The latter three works were each chosen among The New York Times Notable Books of the Year. He published his first book at the age of 44, and achieved favorable critical response.
His 2015 short story collection "Coup de Foudre' features a novela with the same title, it is a thinly veiled fictionalization of Dominique Strauss-Kahn's alleged 2011 sexual assault on a maid in a midtown New York hotel suite. In an interview in Bookslut, he told the critic Vladislav Davidzon "The news often feeds my imagination, which is why my fiction sometimes plays off topical or historical events...."