Cell-extracellular matrix adhesive interactions provide a key regulatory mode of cellular behavior. The molecular basis of adhesion-mediated signaling responses has been under investigation over the past few years. Tyrosine phosphorylation initiated by cell adhesion plays a crucial role in regulating adhesion-mediated signaling and cytoskeletal rearrangement. Oncogenesis involves aberrant interactions between cells and the extracellular matrix. The mechanisms that underline the functions of oncogenes and tumor suppressors often involve modulation of specific tyrosine phosphorylated cytoplasmic proteins, thereby affecting directly adhesion-mediated signaling. The constitutive kinase activity of oncogenes such as v-Src and BCR/Abl hyper-phosphorylates cytoskeletal and signaling molecules, and modulates the functions of integrins, the predominant family of extracellular matrix receptors. The tumor suppressor gene PTEN was recently identified as a key regulator of adhesion-mediated signaling. This review summarizes the direct effects of oncogenes, tumor suppressor genes and their products on the adhesive responses of cells. Understanding of the molecular basis of these effects may provide the means to develop novel therapeutics to control pathological processes associated with aberrant cell-extracellular matrix interactions.