Twin and adoption studies have shown that alcohol dependence contains a substantial genetic component. In attempts to identify the genetic factors involved, association studies have linked the opioid system to alcohol dependence, with a main focus on the OPRM1 gene encoding the mu-opioid receptor. Our aim was to conduct a systematic review of the literature on the associations between polymorphisms in OPRM1 and alcohol dependence. We addressed findings of 12 studies that met our inclusion criteria. All studies employed a case-control design and included alcohol dependence as a dependent outcome measure. Our review showed that clinical studies do not unequivocally support an association between polymorphisms in OPRM1 and alcohol dependence. Factors that complicate genetic research on alcohol dependence, such as gene-environment interaction, and genetic and clinical heterogeneity, are discussed.