In 1999, Lethem published Motherless Brooklyn, a National Book Critics Circle Award-winning novel that achieved mainstream success.

His father was Protestant (with Scottish and English ancestry) and his mother was Jewish, from a family with roots in Germany, Poland, and Russia.

[4][5] His brother Blake became an artist involved in the early New York hip hop scene, and his sister Mara became a photographer, writer, and translator.

29 in nearby Cobble Hill was future New York City Schools Chancellor Carmen Fariña, whom he called the "perfect" teacher and to whom he dedicated his first novel, Gun, with Occasional Music.

[2] He gained an encyclopedic knowledge of the music of Bob Dylan, saw Star Wars 21 times during its original theatrical release,[7] and read the complete works of the science fiction writer Philip K. Dick.

Lethem later said Dick's work was "as formative an influence as marijuana or punk rock—as equally responsible for beautifully fucking up my life, for bending it irreversibly along a course I still travel.

When he was thirteen, his mother Judith died from a malignant brain tumor,[9] an event which he has said haunted him and has strongly affected his writing.

(Lethem discusses the direct relation between his mother and the Bob Dylan song "Like a Rolling Stone" in the 2003 Canadian documentary Complete Unknown.)

"[2] Intending to become a visual artist like his father, Lethem attended the High School of Music & Art in New York, where he painted in a style he describes as "glib, show-offy, usually cartoonish".

He hitchhiked from Denver, Colorado, to Berkeley, California, in 1984, across "a thousand miles of desert and mountains through Wyoming, Utah, and Nevada, with about 40 dollars in my pocket", describing it as "one of the stupidest and most memorable things I've ever done.

"[11] Lethem lived in California for twelve years, working as a clerk in used bookstores, including Moe's and Pegasus & Pendragon Books, and writing on his own time.

[13] Lethem's first novel, Gun, with Occasional Music, is a merging of science fiction and the Chandleresque detective story, which includes talking kangaroos, radical futuristic versions of the drug scene, and cryogenic prisons.

[14] Gun, with Occasional Music was a finalist for the 1994 Nebula Award, and placed first in the "Best First Novel" category of the 1995 Locus Magazine reader's poll.

In the mid-1990s, film producer-director Alan J. Pakula optioned the novel's movie rights, which allowed Lethem to quit working in bookstores and devote his time to writing.

Partially inspired by Lethem's experiences hitchhiking cross-country,[11] this second novel uses a road narrative to explore a multi-post-apocalyptic future landscape rife with perception tricks.

It starts with a physics researcher who falls in love with an artificially generated spatial anomaly called "Lack", for whom she spurns her previous partner.

Lethem credited his comfort in genre-mixing to his father's art, which "always combined observed and imagined reality on the same canvas, very naturally, very un-self-consciously.

"[2] In 2007, he returned as a novelist to California, where some of his earlier fiction had been set, with You Don't Love Me Yet, a novel about an upstart rock band.

The novel revolves around a woman in the band, Lucinda, who answers phones for her friend's complaint line and uses some of a caller's words as lyrics.

According to Lethem, the book was inspired by the years he spent as the lead singer in an upstart California band in the late 1980s and early 1990s, during what he called "the unformed posturing phase of life".

[7] In 2005, Lethem had announced that he was planning to revive the Marvel Comics character Omega the Unknown in a ten-issue series to be published in 2006.

[26] In May 2006, Marvel Editor-in-Chief Joe Quesada explained that the series had been delayed to 2007, saying that "winning the MacArthur Grant put additional and unexpected demands on [Lethem's] time.

[29] In July 2008, Lethem said that Chronic City is "set on the Upper East Side of Manhattan, it's strongly influenced by Saul Bellow, Philip K. Dick, Charles G. Finney and Hitchcock's Vertigo and it concerns a circle of friends including a faded child-star actor, a cultural critic, a hack ghost-writer of autobiographies, and a city official.

He writes, The kernel, the soul—let us go further and say the substance, the bulk, the actual and valuable material of all human utterances—is plagiarism ... Don't pirate my editions; do plunder my visions.

[32] Starting in 2011, he served as the Roy E. Disney Professor in Creative Writing at Pomona College, a position formerly held by the late David Foster Wallace.

Lethem's tenth novel, A Gambler's Anatomy (or, alternatively, The Blot in the United Kingdom), published in October 2016, concerns "an international backgammon hustler who thinks he's psychic".