Tamoxifen is the most common endocrine therapy administered worldwide to women with hormone receptor-positive metastatic breast cancer or as adjuvant therapy for early stages of the disease. Tamoxifen may also be prescribed to women with ductal carcinoma in situ or to decrease the risk of breast cancer in women at high risk of developing the disease. While the use of aromatase inhibitors is increasing in the postmenopausal treatment setting, tamoxifen remains the drug of choice for premenopausal women. Several factors may contribute to reduced benefit from tamoxifen. It has been increasingly recognized in recent years that pharmacogenetics may play a role in tamoxifen's metabolism, efficacy, and safety. Cytochrome P450 (CYP) 2D6 encodes for a liver enzyme that is responsible for the conversion of tamoxifen into its active metabolite, endoxifen. Variant alleles in CYP2D6 or the use of medications that inhibit the enzyme clearly influence tamoxifen's metabolism into endoxifen. In addition, several retrospective studies suggest that variants in CYP2D6 may influence long term outcomes. In this review, we will summarize recent data that examined associations between CYP2D6 activity and effects on tamoxifen's metabolism and efficacy.