Disruption of the cell plasma membrane can occur due to mechanical damage, pore forming toxins, etc. Resealing or plasma membrane repair (PMR) is the emergency response required for cell survival. It is triggered by Ca(2+) entering through the disruption, causing organelles such as lysosomes located underneath the plasma membrane to fuse rapidly with the adjacent plasma membrane. We have recently identified some of the molecular traffic machinery that is involved in this vital process. Specifically, we showed that two members of the Rab family of small GTPases, Rab3a and Rab10, are essential for lysosome exocytosis and PMR in cells challenged with a bacterial toxin, streptolysin-O (SLO). Additionally, we showed that Rab3a regulates PMR via the interaction with two effectors, synaptotagmin-like protein 4 a (Slp4-a) and nonmuscle myosin heavy chain IIA (NMHC IIA), the latter being identified for the first time as a Rab3a effector. This tripartite complex is essential for the positioning of the peripheral lysosomes responsible for PMR. In cells lacking any of the components of this tripartite complex, lysosomes were concentrated in the perinuclear region and absent in the periphery culminating with PMR inhibition.