The selective estrogen receptor modulator tamoxifen has been used for more than three decades to treat metastatic and early-stage receptor-positive breast cancer and, more recently, to prevent the disease. Biotransformation of tamoxifen to the potent antiestrogen endoxifen is performed by cytochrome P450 (CYP) enzymes, in particular the CYP2D6 isoform. Genetic variants in the CYP2D6 gene may result in CYP2D6 enzymes with reduced or null activity. Strong and intermediate inhibitors of CYP2D6, which may be used to treat hot flashes or psychiatric conditions in breast cancer patients, can also negatively impact enzyme function. Prospective data are lacking, but the balance of current evidence strongly suggests that, compared with women with two wild-type alleles, the presence of two null alleles, and possibly one null allele, predicts reduced tamoxifen metabolism and an inferior outcome in postmenopausal women with early breast cancer who receive adjuvant treatment with the drug. Unfortunately, studies to date have been largely retrospective and the interpretation of their results is limited by examination of archival tissue samples and the inclusion of heterogeneous populations. Although we do not currently recommend routine CYP2D6 testing for women who do not have alternative standard therapies, the use of concomitant strong or intermediate inhibitors of CYP2D6 should be avoided if feasible. This review summarizes the literature to date with a focus on clinically relevant recent studies that examined the association between CYP2D6 polymorphisms and tamoxifen-associated outcomes.