The G-protein coupled receptors for Δ9-tetrahydrocannabinol, the major psychoactive principle of marijuana, are known as cannabinoid receptors of type 1 (CB1) and 2 (CB2) and play important functions in degenerative and inflammatory disorders of the central nervous system. Whilst CB1 receptors are mostly expressed in neurons, where they regulate neurotransmitter release and synaptic strength, CB2 receptors are found mostly in glial cells and microglia, which become activated and over-express these receptors during disorders such as Alzheimer's disease, multiple sclerosis, amyotropic lateral sclerosis, Parkinson's disease, and Huntington's chorea. The neuromodulatory actions at CB1 receptors by endogenous agonists (‘endocannabinoids’), of which anandamide and 2- arachidonoylglycerol are the two most studied representatives, allows them to counteract the neurochemical unbalances arising during these disorders. In contrast, the immunomodulatory effects of these lipophilic mediators at CB2 receptors regulate the activity and function of glia and microglia. Indeed, the level of expression of CB1 and CB2 receptors or of enzymes controlling endocannabinoid levels, and hence the concentrations of endocannabinoids, undergo time- and brain region-specific changes during neurodegenerative and neuroinflammatory disorders, with the initial attempt to counteract excitotoxicity and inflammation. Here we discuss this plasticity of the endocannabinoid system during the aforementioned central nervous system disorders, as well as its dysregulation, both of which have opened the way to the use of either direct and indirect activators or blockers of CB1 and CB2 receptors for the treatment of the symptoms or progression of these diseases.