The calcium-dependent thiol proteases, calpains, are widely expressed with ubiquitous and tissue specific isoforms. Calpains have been implicated in basic cellular processes including cell proliferation, apoptosis and differentiation. The focus of the current review is to summarize recent findings implicating calpains in cytoskeletal rearrangements and cell migration. Calpain cleaves many cytosolic proteins and therefore to be effective and limited in its scope, calpain activity has to be tightly regulated both temporally and spatially. Some mechanisms of regulation include calcium, growth factor-mediated phosphorylation and membrane targeting. Calpain inhibition reduces migration rates and inhibits cell invasiveness. Two putative mechanisms of calpain action during migration include its role as a signaling intermediate, acting upstream of Rho, and its effects on focal adhesion structure and disassembly. Therefore, calpains and downstream signaling molecules may be future targets for therapeutic interventions to treat cancer or chronic inflammation.