Cellular damage triggers rapid resealing of the plasma membrane and repair of the cortical cytoskeleton. Plasma membrane resealing results from calcium-dependent fusion of membranous organelles and the plasma membrane at the site of the damage. Cortical cytoskeletal repair results from local assembly of actin filaments (F-actin), myosin-2 and microtubules into an array that closes around the original wound site. Control of the cytoskeletal response is exerted by local activation of the small GTPases, Rho and Cdc42. Recent work has given insight into both the membrane fusion and cytoskeletal responses to plasma membrane damage and we propose that Rho GTPase activation results at least in part from the events that drive membrane repair.