Transforming growth factor-β (TGF-β) is an important physiologic regulator of cell growth and differentiation. TGF-β has been shown to inhibit the proliferation of quiescent hematopoietic stem cells and stimulate the differentiation of late progenitors to erythroid and myeloid cells. Insensitivity to TGF-β is implicated in the pathogenesis of many myeloid and lymphoid neoplasms. Loss of extracellular TGF receptors and disruption of intracellular TGF-β signaling by oncogenes is seen in a variety of malignant and premalignant states. TGF-β can also affect tumor growth and survival by influencing the secretion of other growth factors and manipulation of the tumor microenvironment. Recent development of small molecule inhibitors of TGF-β receptors and other signaling intermediaries may allow us to modulate TGF signaling for future therapeutic interventions in cancer.