Scaffolding proteins are thought to facilitate the efficiency and specificity of enzyme/substrate reactions by coordinating their interaction along a cytoskeletal infrastructure in a spacial and temporal manner. Rodent SSeCKS, and its human orthologue, Gravin, seem to function as tumor suppressors and regulators of mitogenesis, inflammatory response, development and differentiation via novel scaffolding functions involving the selective binding of key G1–>S phase signaling proteins such as protein kinase C (PKC), PKA, calmodulin, cyclins and ß-adrenergic receptors. The association of SSeCKS/Gravin with the actin-based cytoskeleton as well as to plasma membrane sites via N-terminal myristylation places these proteins at the junction of signaling and cytoskeletal pathways. The following review describes the regulatory and scaffolding functions of SSeCKS and Gravin and how mitogen-induced phosphorylation modulates their ability to regulate cell adhesion, signaling, mitogenesis and oncogenesis.