The signal transducer and activator of transcription (STAT) proteins and their mechanisms of signaling were originally discovered in the context of normal interferon signaling, where they have been shown to have specific roles in mediating host defenses. It is now known that many cytokines, hormones and growth factors utilize STAT signaling pathways to control a remarkable variety of biological responses, including development, differentiation, cell proliferation, and survival. Given the critical roles of STAT proteins in these fundamental cellular processes, which are often altered in cancer, there is accumulating evidence defining a critical role for STAT proteins in oncogenesis. Members of this relatively small family of proteins serve as both transducers of cytoplasmic signals and nuclear transcription factors, thereby directly converting a stimulus at the cell surface to an alteration in the genetic program. Moreover, STAT proteins can cross-talk with other central signaling pathways, such as the mitogen-activated protein kinase (MAPK) family of proteins and the nuclear receptor signaling pathways. On the othe r hand, other proteins are known to interact with and modulate STAT signaling pathways, including histone acetyl-transferases and the protein inhibitor of activated STAT (PIAS) family of protein. The present review will try to address some questions concerning the increasingly complex biological functions of STAT proteins, the many diverse mechanisms of STAT regulation and the expanding number of target genes that mediate the biological responses elicited by STAT signaling pathways.