Cell life is defined by a thin 4 nm plasma membrane, which separates the interior of a cell from its environment. Thus, disruption of the plasma membrane poses a critical risk to cells, which requires immediate repair to avoid uncontrolled osmotic lysis and cell death. The initial repair response to stop the leakage usually occurs within 10–45 s and implicates Ca²⁺-activated phospholipid-binding proteins including annexins. We previously reported that annexin-induced curvature of lateral membrane around the hole plays an important role for immediate resealing of human cancer cells. Once the breach has been sealed, the cell often regenerates itself by removing the damaged membrane. This process, which also involves annexins includes excision and shedding of damaged membrane implicating the endosomal sorting complex required for transport (ESCRT) III and actin cytoskeleton remodeling. Hence, studies of cell membrane repair mechanisms should differentiate between the immediate repair response happening within seconds and the subsequent regeneration phase, which occurs in the order of minutes to hours after injury.