Monoacylglycerol lipase (MAGL) has been recently proposed as the main enzymatic activity responsible for the in vivo hydrolysis of the most abundant endocannabinoid in the brain, the 2-arachidonoylglycerol (2-AG). The endocannabinoids, mainly anandamide (AEA) and 2-AG, are a class of lipid messengers that modulate a broad number of physiological processes both in the central nervous system and in the periphery. To date, AEA has been by far the most studied endocannabinoid, although increasing evidence is pointing out the prominent, and sometimes underestimated, role of 2-AG in the regulation of different functions. Therefore, it is of outmost importance to dissect the specific cellular pathways in which these two endocannabinoids are involved. Nonetheless, little is known about the structural requirements of MAGL. Here we review the current knowledge on MAGL, with special focus on its structure and catalytic mechanism as the rational basis for the design of potent and selective compounds able to interact with it; the inhibitors that have been described to date, and the therapeutic applications that make MAGL an attractive therapeutic target.