Updated project metadata. Toxoplasma gondii is able to establish a life-long chronic infection in human and animals. Host cell entry and egress from infected cells are two key steps in the lytic cycle of this obligate intracellular parasite that ensures its survival and dissemination. Egress is a temporally orchestrated process underpinned by the regulated exocytosis of the apical secretory organelles, termed micronemes. At any point during intracellular replication, deleterious environmental changes resulting from a loss of host cell integrity can trigger egress via the activation of the cGMP-dependent protein kinase G (PKG). Remarkably, even in the absence of extrinsic alarming signals, the parasites naturally egress from infected cells in a coordinated manner after ca. 5 to 6 cycles of binary fission. Here we show that diacylglycerol kinase 2 (DGK2) is secreted into the parasitophorous vacuole where it produces phosphatidic (PA), which acts as intrinsic signal to elicit natural egress. PA activates a large guanylate cyclase (GC) receptor uniquely conserved in apicomplexans and composed of one P4-ATPase and two guanylate cyclase domains. Assembly of a functional GC at the parasite plasma membrane critically depends on the association with two proteins acting as cofactors. This study reveals the existence of a unique and versatile signaling platform able to respond to an intrinsic lipid mediator and other extrinsic alarming signals to control programmed and induced egress, respectively.