The brain endocannabinoid system (ECS) plays an essential role in regulating central physiological processes that underlie learning and memory, anxiety, depression, addiction, appetite and feeding, pain, neuronal excitability and protection. A primary mode through which the ECS functions in the brain is via its regulation of synaptic transmission, whereby neuronal depolarization triggers the on-demand synthesis and release of the endocannabinoids anandamide and 2-arachidonylglycerol, which act in a retrograde manner at presynaptic cannabinoid type I receptors to inhibit transmitter release. The actions of the brain ECS occur in a highly complex temporal and spatial manner, which enable it to fine-tune neuronal transmission at the regional, neuronal-network pathways, synaptic, and cellular/molecular levels. In this effect, the ECS can be recruited as a defense mechanism against excitotoxic neuronal transmission. Research studies have revealed that in the neuropathological conditions of seizure and epilepsy, lasting alterations in the ECS occur, which may act in a compensatory manner to regulate the neuronal hyperexcitability associated with these disorders. This chapter will cover the current knowledge of the underlying processes through which the brain ECS regulates excitatory synaptic transmission and the maladaptive alterations to this endogenous system that have been shown to be associated with the epileptic condition. Lastly, the wealth of basic research findings that has utilized in vivo and in vitro models to evaluate the therapeutic potential for targeting different components of the brain ECS for the treatment of seizures and epilepsy, as well as a brief addressing of anecdotal data on the use of cannabinoid-based medicines for the treatment of these clinical conditions, will be discussed.