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The development of cancer is a complex process involving multiple stages. This Review, with 2 figures and 49 references, describes how changes in cellular morphology or shape can contribute to oncogenesis. The focus is epithelial cell shape and how the various specialized membrane regions sequester receptor subunits and may segregate receptors from their ligands, thereby controlling cell behavior. When epithelial cell morphology is disrupted, aberrant signaling leading to cell proliferation and transition from an epithelial to a more motile mesenchymal phenotype may occur. We further suggest that this mechanism for oncogenesis recapitulates a normal epithelial response to sense and repair damage. We focus on the receptors of the epidermal growth factor family and transforming growth factor–β family as examples of receptor sequestration and segregation, and we describe how these two receptors may contribute to oncogenesis.