Candidate gene studies on smoking behaviors mainly focused on dopaminergic and serotonergic genes, but genes within the µ-opioid system might also be involved. The A118G variant within the OPRM1 gene has been most often examined in relation to smoking, yielding inconsistent findings. It is largely unknown which of the alleles increases susceptibility for smoking behaviors. The aim of this review was to merge findings of OPRM1 gene studies in relation to smoking behaviors and to elaborate on the underlying biological mechanism of the A118G variant. It appeared that A118 was more likely to increase susceptibility to smoking behaviors than 118G, especially with regard to nicotine dependence, but less with smoking initiation and cessation. The proposed functioning of the OPRM1 gene is further explained.