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Weiss nasceu e cresceu em Chicago, Illinois, se formou na Universidade Wesleyan, conseguiu um Mestrado de Filosofia em literatura irlandesa do Trinity College, Dublin e um Mestrado em Belas Artes da Iowa Writers' Workshop.
Em 2003, Weiss publicou seu primeiro livro, Lucky Wander Boy.
Em 2011 ele criou, junto com seu amigo David Benioff, a série de televisão Game of Thrones, baseada na série de livros As Crônicas de Gelo e Fogo escritos por George R. R. Martin. Weiss atua como produtor executivo e roteirista da série.
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