BACKGROUND AND OBJECTIVES:Drug addiction is a serious illness with deleterious functional and social consequences for both the affected individuals, their families, and society at large. In spite of the abundant research on substance dependence, there are few effective treatments for this disease. Given the crucial role of the endogenous opioid system in the development and maintenance of substance abuse disorders, this review focuses on the opioidergic system and examines the role of opioidergic genes in the treatment outcome of pharmacotherapies of alcohol, opioid, and cocaine addiction. METHODS:Scopus (all databases) and Pubmed were systematically searched with no language or year restrictions, up to July 2014, for studies that focused on the relationship between polymorphisms of opioidergic genes and the treatment outcome of pharmacotherapies of alcohol, opioid, and cocaine addictions. Selected search terms were opioid, gene, polymorphism, drug therapy, substance abuse, and response. RESULTS AND CONCLUSIONS:The genetic variability of μ-, δ- and κ-opioid receptors genes OPRM1, OPRD1, and OPRK1 modulates the efficacy of opioid antagonist treatments such as naltrexone and methadone, as well as the cocaine vaccine. Despite the number of promising reports, data from additional cohorts are needed to substantiate these findings. SCIENTIFIC SIGNIFICANCE:Gene variant profiling could help predict treatment response and assist in developing effective treatments for alcohol, opioid, and cocaine addiction.