Many proteins that have been implicated in cell-matrix adhesion and cell migration are phosphorylated, which regulates their folding, enzymatic activities and protein-protein interactions. Although modulation of cell motility by kinases is well known, increasing evidence confirms that phosphatases are essential at each stage of the migration process. Phosphatases can control the formation and maintenance of the actin cytoskeleton, regulate small GTPase molecular switches, and modulate the dynamics of matrix-adhesion interaction, actin contraction, rear release and migratory directionality.