To egress out of the host red blood cell, the daughter parasites must rupture two sequential membranes: the parasitophorous vacuolar membrane (PVM) and host cell plasma membrane (PM). The trigger for the egress pathway(s) remains unknown. The cytoplasmic concentrations of the two dominant second messengers, calcium and cyclic GMP (cGMP), begin the cascade of egress. Increased cGMP activates protein kinase G (PKG), which phosphorylates proteins important for apical organelle release. PKG also interacts with the phosphoinositide signaling pathway that likely leads to calcium release from the endoplasmic reticulum (ER). Increased cytoplasmic calcium activates the calcium-dependent protein kinases (CDPKs), especially CDPK5,which also facilitates apical organelle secretion. Triggered secretion of the exoneme releases subtilisin-like protease 1 (SUB1) into the parasitophorous vacuole (PV). Activated SUB1, together with other proteases, leads to the disruption of the PVM first and the host plasma membrane second. Solid arrows indicate direct links; dashed arrows indicate indirect links or links with un Dvorin JD, Goldberg DE. Plasmodium Egress Across the Parasite Life Cycle. Annu Rev Microbiol. 2022 76:67-90 PMID: 35417197