Although the signal transducer and activator of transcription (STAT) proteins were originally discovered through the study of interferon-induced responses, a large number of cytokines and growth factors have been found to activate STATs. In addition to the fundamental role of STAT pathways in normal cell signaling, accumulating evidence is defining a critical role for STATs in oncogenesis. STAT family members are constitutively activated by various oncoproteins in transformed cells and are found activated in a wide variety of human tumors, including breast cancer and diverse blood malignancies. This review discusses recent progress in understanding how aberrant activation of STAT signaling pathways participates in malignant progression of human cancers. Current evidence indicates that one mechanism by which STATs contribute to oncogenesis involves prevention of programmed cell death, or apoptosis, thereby conferring a survival advantage and, potentially, resistance to chemotherapy. These advances identify STATs as novel molecular targets for development of promising therapeutics against human cancers that harbor activated STAT proteins.