Endocannabinoid-signaling chains have been implicated in a variety of pathophysiological functions, including memory, coordination, vasoregulation, reproduction, neurodegeneration, and inflammation. These activities were thought to be mediated by the activation of two G-protein-coupled receptors (GPCRs), type 1 and type 2 cannabinoid receptors (CB(1)R and CB(2)R). These two CBR subtypes share common agonists and trigger similar signaling pathways, yet they present several important differences in structure and cell distribution. In particular, recent research has shown that the CB(1)R and CB(2)R are differentially linked to lipid rafts, specialized microdomains of the plasma membrane involved in the signaling of many other GPCRs. We present an overview of the current literature on the effects that lipid raft perturbation have on CBRs activities, and provide a mechanistic model to interpret these data in terms of structural and functional aspects. These findings may also have important implications for the development of new therapeutic approaches, including lipid raft perturbing drugs, aimed to selectively modulate CB(1)R signaling in a variety of pathological conditions.