Cellular homeostasis is tightly controlled by the various pathways that regulate cell proliferation and cell death. Breaking this balance is often associated with cancer development. The transforming growth factor-beta (TGF-beta) pathway plays an important role in cellular homeostasis by regulating cell growth inhibition, cellular senescence, differentiation and apoptosis. Deregulated TGF-beta signaling is known to be involved in a variety of human cancers, including those of the colon, pancreas, breast and prostate. While TGF-beta is a potent negative regulator of hematopoiesis, the role of aberrant TGF-beta signaling in leukemogenesis remains largely unknown. Recently, evidence demonstrating deregulated TGF-beta signaling in leukemogenesis, particularly in acute promyelocytic leukemia (APL), has started to emerge. In this review, we summarize the current progress towards the understanding of the molecular mechanisms by which aberrant TGF-beta signaling may participate in leukemogenesis.