Regulation of cell migration/invasion is important for embryonic development, immune function, and angiogenesis. However, migratory cells must also coordinately activate survival mechanisms to invade the extracellular matrix and colonize foreign sites in the body. Although invasive cells activate protective programs to survive under diverse and sometimes hostile conditions, the molecular signals that regulate these processes are poorly understood. Evidence is provided that signals that induce cell invasion also promote cell survival by suppressing apoptosis of migratory cells. Extracellular-regulated kinase (ERK) activation and molecular coupling of the adaptor proteins p130 Crk-associated substrate (CAS) and c-CrkII (Crk) represent two distinct pathways that induce cell invasion and protect cells from apoptosis in a three-dimensional collagen matrix. CAS/Crk-mediated cell invasion and survival requires activation of the small GTPase Rac, whereas ERK-induced cell invasion, but not survival requires myosin light chain kinase activation and myosin light chain phosphorylation. Uncoupling CAS from Crk or inhibition of ERK activity prevents migration and induces apoptosis of invasive cells. These findings provide molecular evidence that during invasion of the extracellular matrix, cells coordinately regulate migration and survival mechanisms through ERK activation and CAS/Crk coupling.