The endocannabinoid system (ECS) is a ubiquitous modulatory neurotransmission system composed of different endogenous ligands, receptors, and enzymes of synthesis and metabolization involved in various brain functions. The discovery of these elements has stimulated the search for new targets as a potential therapeutic approach for a variety of diseases, such as substance use disorders (SUD), with promising results. The chapter reviews the primary evidence available from animal models and clinical studies on how components of the ECS are modified in different SUD and how the genetic and pharmacological modulation of the ECS modified the reinforcing, motivational, and withdrawal-related effects of alcohol, cocaine, opioids, and cannabis. Finally, this chapter provides concluding remarks about the future challenges required to develop safe and effective new drugs acting on the most promising components of the ECS to treat SUD.