Cells in multicellular organisms are under constant mechanical stress, and often the plasma membrane (PM) is compromised. Fortunately, there is a vigorous repair mechanism that rapidly (within seconds) reseals the wound site by fusion with an internal membrane patch. Downstream events, remodeling of the injury site and forming replacement PM, must be carried out quickly (within minutes) if a cell is to survive multiple sequential injuries. The repertoire of proteins required to repair breaks (the PM repairome) is one of the major unknowns in this area of research. As an initial approach to defining the PM repairome, a cell surface biotinylation protocol was developed to identify intracellular proteins that become exposed at the site of reversible PM injury. It is likely that at least some of these proteins are important mediators of repair. These initial studies led to a surprising finding, namely the identification of some nuclear and endoplasmic reticulum resident proteins transiently exposed at the surface of cells that ultimately recovered from PM damage. Thus, in reversible mechanical damage to the PM, underlying cellular structures may also be injured, and will also require mechanisms for repair. Other proteins at wound sites were previously identified docking partners for pathogenic bacteria and viruses (vimentin and nucleolin), or found to be upregulated and exposed on the surface of cancer cells (nucleolin and nucleophosmin-1). The new information from these studies may lead to development of novel antimicrobial and antineoplastic drugs.