Recently, the xenobiotic hypothesis has implicated the immune system in targeting substances of abuse as foreign molecules and stimulating inflammatory responses. Microglial cells are the resident immune cells of the central nervous system and function in homeostatic surveillance. Microglial changes that are induced by exposure to substances of abuse appear to mediate in part the establishment of addiction and the persistence of drug-mediated biological and behavioral changes. In this context, interest in the study of drug-microglia interactions has increased recently. This review summarizes the most recent preclinical rodent and clinical studies on the interaction between microglia and various classes of drugs of abuse, such as ethanol, psychostimulants, and opioids. The principal biological mechanisms of the communication between substances of abuse and microglia will be described to consider putative mechanisms of the establishment of drug addiction and future potential targets for treating substance use disorder.