TGF-beta signaling regulates tumorigenesis and in human cancer its signaling pathways are often modified during tumor progression. Prior to initiation and early during progression TGF-beta acts upon the epithelium as a tumor suppressor, however at later stages it is often a tumor promoter. Over the years, many studies have focused on the epithelial cell autonomous role for TGF-beta, however, TGF-beta is not strictly limited to this compartment in vivo. Recent studies addressing TGF-beta mediated stromal-epithelial interactions have significantly improved our understanding related to the regulation of cancer. In addition, stromal fibroblast cell autonomous effects have been observed in response to TGF-beta stimulation. According to the current literature and experimental evidence, TGF-beta is a potent ligand that regulates carcinoma initiation, progression and metastasis through a broad and complex spectrum of interdependent interactions.