The late writer David Foster Wallace hailed Wittgenstein's Mistress as "pretty much the high point of experimental fiction in this country".

[3] While his early works draw on the modernist tradition of William Faulkner and Malcolm Lowry, his later novels are, in Markson's words, "literally crammed with literary and artistic anecdotes" and "nonlinear, discontinuous, collage-like, an assemblage.

"[13] A decade later, David Foster Wallace described it as "pretty much the high point of experimental fiction in this country" in an article for Salon entitled "Five direly underappreciated U.S. novels >1960.

Most of the traditional comforts of the novel form are absent, as an author-figure closely identified with Markson himself[20] considers the travails of the artist throughout the history of culture.

His working process involved "scribbling the notes on three-by-five-inch index cards" and collecting them in "shoebox tops" until they were ready to be put "into manuscript form.

Of Reader's Block, fellow writer and friend Kurt Vonnegut wrote, "David shouldn’t thank Fate for letting him write such a good book in a time when large numbers of people could no longer be wowed by a novel, no matter how excellent."

"[23] This seemingly-random set of quotes, ideas, and nuggets of information about the lives of various literary, artistic, and historical figures cohere to form a new kind of novel.