Endogenous cannabinoid signaling is an important neuromodulatory system with widespread impact across the brain. The endocannabinoid signaling system is composed of the cannabinoid receptors, endogenous ligands for the receptors (endocannabinoids), and the enzymes that are responsible for endocannabinoid synthesis and degradation. Within the brain, components of the endocannabinoid signaling system are expressed in neurons, the cerebral vasculature, and glial cells, and they modulate neurodevelopment, blood flow, and synaptic activity. As a result of this widespread presence, it is not an exaggeration to state that endocannabinoid signaling contributes significantly to all aspects of brain function. As components of the cannabis plant, such as Δ9-tetrahydrocannabinol (Δ9-THC), act through cannabinoid receptors and modulate endocannabinoid signaling, knowledge about this system is important in understanding the impact of cannabis use. In this chapter, we discuss the components of the endocannabinoid system, their regulation, and the role of the endocannabinoid system in regulating synaptic function, stress responses, and behavior.