TGF-β is a multifunctional cytokine that plays an essential role in regulating mammary gland development, morphogenesis, differentiation and involution. TGF-β also regulates mammary gland homeostasis and prevents its transformation by prohibiting dysregulated cell cycle progression and inducing apoptosis; it also creates cell microenvironments that readily inhibit cell migration, invasion and metastasis. Interestingly, while early-stage mammary tumors remain sensitive to the tumor-suppressing activities of TGF-β, late-stage breast cancers become insensitive to the anticancer functions of this cytokine and instead rely upon TGF-β to drive disease and metastatic progression. This switch in TGF-β function is known as the ‘TGF-β paradox’ and represents the rationale for developing chemotherapies to inactivate the TGF-β pathway and its oncogenic functions in late-stage breast cancers. Here we outline the molecular mechanisms that manifest the TGF-β paradox and discuss the challenges associated with the development and use of anti-TGF-β agents to treat breast cancer patients.