Different classes of neurons in the CNS utilize endogenous cannabinoids as retrograde messengers to shape afferent activity in a short- and long-lasting fashion. Transient suppression of excitation and inhibition as well as long-term depression or potentiation in many brain regions require endocannabinoids to be released by the postsynaptic neurons and activate presynaptic CB1 receptors. Memory consolidation and/or extinction and habit forming have been suggested as the potential behavioral consequences of endocannabinoidmediated synaptic modulation. However, endocannabinoids have a dual role: beyond a physiological modulation of synaptic functions, they have been demonstrated to participate in the mechanisms of neuronal protection under circumstances involving excessive excitatory drive, glutamate excitotoxicity, hypoxia-ischemia, which are key features of several neurodegenerative disorders. In this framework, the recent discovery that the endocannabinoid 2-arachidonoyl-glycerol is released by midbrain dopaminergic neurons, under both physiological synaptic activity to modulate afferent inputs and pathological conditions such as ischemia, is particularly interesting for the possible implication of these molecules in brain functions and dysfunctions. Since dopamine dysfunctions underlie diverse neuropsychiatric disorders including schizophrenia, psychoses, and drug addiction, the importance of better understanding the correlation between an unbalanced endocannabinoid signal and the dopamine system is even greater. Additionally, we will review the evidence of the involvement of the endocannabinoid system in the pathogenesis of Parkinsons disease, where neuroprotective actions of cannabinoid-acting compounds may prove beneficial. The modulation of the endocannabinoid system by pharmacological agents is a valuable target in protection of dopamine neurons against functional abnormalities as well as against their neurodegeneration.