Monoacylglycerol lipase (MAGL) and a/b hydrolase domain-containing protein (ABHD) have been recently identified as key enzymes in the hydrolysis of 2-arachidonoylglycerol (2-AG), one of the endocannabinoids (eCBs) in the brain. Brain MAGL generates free fatty acids such as arachidonic acid, which regulate proinflammatory cytokine production or termination of eCB-mediated synaptic retrograde signaling. It has been elucidated that dysfunction of MAGL and eCB metabolism are involved in several neurodegeration models via distinct mechanisms. ABHD6 is also important for tuning of 2-AG signaling in synaptic function. ABHD12 encodes serine hydrolase, mutations in which cause the neurodegenerative disorder PHARC (polyneuropathy, hearing loss, ataxia, retinosis pigmentosa, and cataract), and is involved in microglial homeostasis. Recent advances in our understanding of these eCB-metabolizing enzymes have complemented existing studies of eCB receptors in development and neurodegeneration models.