Signal transducer and activator of transcription (STAT) proteins comprise a family of transcription factors that are activated by cytokines, hormones and growth factors. The activation of STAT proteins plays a key role in the production of mature hematopoietic cells via effects on cellular proliferation, survival and lineage-specific differentiation. Emerging evidence also demonstrates frequent, constitutive activation of STATs in primary leukemia specimens. Moreover, roles for STATs in promoting leukemia development have been delineated in numerous preclinical studies. This review summarizes our current understanding of STAT protein involvement in normal hematopoiesis and leukemogenesis, as well as recent advances in the development and testing of novel STAT inhibitors.