There is clear evidence that CB2, historically referred to as the peripheral cannabinoid receptor, mediates many of the immune modulatory effects of cannabinoids. However, cannabinoid receptors cannot be classified simply as central or peripheral since CB2 has been shown to play a role in the central nervous system (CNS) and CB1 mediates many immune system effects. Although Cnr1 mRNA and CB1 protein expression is lower than Cnr2 mRNA or CB2 protein expression in cells of the immune system, several studies have shown direct modulation of immune function via CB1 by endogenous and exogenous cannabinoids in T cells, innate cells, and to a lesser extent, B cells. In addition, indirect, but CB1-dependent, mechanisms of immune modulation exist. In fact, the mechanism by which cannabinoids attenuate neuroinflammation via CB1 is likely a combination of immune suppression and neuroprotection. Although many studies demonstrate that agonists for CB1 are immune suppressive and anti-inflammatory, CB1 antagonists also exhibit anti-inflammatory properties. Overall, the data demonstrate that many of the immune modulatory effects of cannabinoids are mediated via CB1.