Endocannabinoids are released from postsynaptic neurons, activate presynaptic cannabinoid receptors and cause various forms of short-term and long-term synaptic plasticity throughout the brain. Using hippocampal and cerebellar neurons, we have revealed that endocannabinoid release can be induced through two different pathways. One is independent of phospholipase C (PLC) and driven by Ca²⁺ elevation alone (Ca²⁺-driven endocanabinoid release, CaER), and the other is PLC-dependent and driven by activation of G_q/11-coupled receptors (receptor-driven endocannabinoid release, RER). CaER is induced by activation of either voltage-gated Ca²⁺ channels or NMDA receptors. RER is functional even at resting Ca²⁺ levels (basal RER), but markedly enhanced by a small Ca²⁺ elevation (Ca²⁺-assisted RER). In Ca²⁺-assisted RER, PLC serves as a coincidence detector of receptor activation and Ca²⁺ elevation. We have also demonstrated that Ca²⁺-assisted RER is essential for the endocannabinoid release triggered by synaptic activity. Our anatomical data show that a set of receptors and enzymes required for RER are well organized so that the excitatory input can trigger RER effectively. Certain forms of spike-timing-dependent plasticity (STDP) are reported to depend on endocannabinoid signaling. The NMDA receptor and PLC might play key roles in the endocannabinoid-dependent forms of STDP as coincidence detectors with different timing dependences.