There is considerable complexity underlying the mechanisms through which the TGF-beta signaling pathway regulates the initiation and progression of cancer. Analysis of this pathway and the role that it plays in human malignancy continues to elucidate novel mechanisms through which various genetic and epigenetic events subvert the controls that TGF-beta exerts over cell growth, differentiation, and malignant transformation. Modeling these events in the mouse represents an important goal, as the relevant preclinical models are essential not only for improving our understanding of the role of the TGF-beta pathway in the molecular pathogenesis of cancer, but also as tools for evaluating the impact of novel therapeutics on TGF-beta signaling and the role they may play in the prevention and treatment of malignancies. Here, we consider highlights from a number of in vivo murine model systems and relate a few of the significant observations to what we know about TGF-beta signaling in human cancer.