Tamoxifen has been used as adjuvant hormonal therapy for estrogen receptor positive breast cancer for over 30 years and is also widely used for the treatment of metastatic breast cancer. Tamoxifen is metabolized to its more active form by cytochrome P450 2D6 (CYP2D6); decreases in CYP2D6 activity, either by inactivating polymorphisms or drug interactions, can reduce concentrations of tamoxifen's active metabolites. Clinical studies demonstrate that breast cancer patients treated with adjuvant tamoxifen who have decreased CYP2D6 due to genetic polymorphisms or drug interactions may have an increased risk of recurrence and reductions in disease-free survival. Pharmacogenetic testing is currently available to predict CYP2D6 phenotypes and individualize tamoxifen therapy.