Transforming growth factor-β (TGF-β) mediates numerous biological processes, including embryonic development and the maintenance of cellular homeostasis in a context-dependent manner. Consistent with its central role in maintaining cellular homeostasis, inhibition of TGF-β signaling results in disruption of normal homeostatic processes and subsequent carcinogenesis, defining the TGF-β signaling pathway as a tumor suppressor. However, once carcinogenesis is initiated, the TGF-β signaling pathway promotes cancer progression. This dichotomous function of the TGF-β signaling pathway is mediated through altering effects on both the cancer cells, by inducing apoptosis and inhibiting proliferation, and the tumor microenvironment, by promoting angiogenesis and inhibiting immunosurveillance. Current studies support inhibition of TGF-β signaling either alone, or in conjunction with anti-angiogenic therapy or immunotherapy as a promising strategy for the treatment of human cancers.