Signal transducer and activator of transcription (STAT) proteins are a 7-member family of cytoplasmic transcription factors that contribute to signal transduction by cytokines, hormones, and growth factors. STAT proteins control fundamental cellular processes, including survival, proliferation, and differentiation. Given the critical roles of STAT proteins, it was hypothesized that inappropriate or aberrant activation of STATs might contribute to cellular transformation and, in particular, leukemogenesis. Constitutive activation of mutated STAT3 has in fact been demonstrated to result in transformation. STAT activation has been extensively studied in leukemias, and mechanisms of STAT activation and the potential role of STAT signaling in leukemogenesis are the focus of this review. A better understanding of mechanisms of dysregulation of STAT signaling pathways may serve as a basis for designing novel therapeutic strategies that target these pathways in leukemia cells.