Transforming growth factor (TGF)-β cytokines signal via a complex network of pathways to regulate proliferation, differentiation, adhesion, migration, and other functions in many cell types. A high percentage of colorectal tumors contain mutations that disrupt TGF-β family member signaling. We review how TGF-β family member signaling is altered during development of colorectal cancer, models of study, interaction of pathways, and potential therapeutic strategies.