STAT proteins are a family of eukaryotic transcription factors that mediate the response to a large number of cytokines and growth factors. Upon activation by cell-surface receptors or their associated kinases, STAT proteins dimerize, translocate to the nucleus and bind to specific promoter sequences on their target genes. Here we report the first crystal structure of a STAT protein bound to its DNA recognition site at 2.25 A resolution. The structure provides insight into the various steps by which STAT proteins deliver a response signal directly from the cell membrane to their target genes in the nucleus.