Signal transducers and activators of transcription (STAT) regulate a plethora of cytokine responses. Recently, aberrant signaling by STAT proteins has been demonstrated to play important roles in the pathogenesis of many neoplasms, by promoting cell cycle progression and survival, stimulating angiogenesis, and impairing immunological responses and tumor surveillance. We have developed genetic tools to evaluate STAT-dependent malignancy and showed that survival and growth of lymphoid malignancies requires expression of STAT3. In contrast, loss of STAT3 in normal cells does not impair their growth or survival; but in spite of this apparent dispensability of STAT3, STAT3-null fibroblasts are resistant to transformation by a variety of oncogenes. The precise molecular mechanisms responsible for the tumorigenic activity of STAT3 have been only partially elucidated. While the tyrosine phosphorylation of STAT3, which is indicative of its signal-dependent activation, is a common occurrence in tumors, and appears to play a crucial role in some malignancies, a variety of new data suggest that it can be dispensable under some circumstances and STAT3 can participate in transformation through novel and non-canonical mechanisms. The discovery and dissection of non-canonical modes of STAT3 action will open new avenues for the design of effective therapeutics capable of neutralizing the tumorigenic properties of this molecule.