It is widely recognized that growth factors play critical roles in cell proliferation and differentiation. In the early 1980s, several members of the transforming growth factor-beta (TGF-beta) superfamily were identified and subsequently shown to play important roles in many diseases, in particular cancer. Efforts to understand how TGF-beta exerts its effects led to identification of TGF-beta-receptors and several downstream signaling pathways activated by this family of growth factors. This review provides an overview of TGF-beta-receptors and its downstream signaling pathways. As part of this discussion, this review indicates that inactivation of TGF-beta-receptors or components of their signaling pathways is often a target during carcinogenesis and that mutations or altered expression at any step along this complex, growth regulatory pathway can lead to aberrant cell proliferation. Lastly, the Cancer Genome Anatomy Project is briefly discussed, in particular how it may help to identify aberrant growth factor expression during carcinogenesis and improve the diagnosis of cancer patients.