He was born in the Bronx, NY and grew up in Plainview, Long Island.

Kalfus started college at Sarah Lawrence College, Bronxville, NY, but dropped out after the first year. He attended various other universities including the New School for Social Research in Manhattan and Trinity College in Dublin, Ireland. Kalfus started writing at an early age.

Kalfus and his family have lived in Paris, Dublin, Belgrade, and Moscow. He believes his time in other countries keeps his observations fresh and provides him with valuable insights.

He is the author of several books, after beginning with publishing short stories. His most recent novel was A Disorder Peculiar to the Country (2006), 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.

The 2007 HBO movie Pu-239 was based on his short story of the same name.

He is married to a journalist and has a daughter.