Tamoxifen, a selective estrogen receptor modulator, is the standard of care for premenopausal women with estrogen or progesterone receptor-positive breast cancer and a valid option for treating post-menopausal women. However, a substantial number of tamoxifen-treated patients relapse following surgical resection, while others remain disease-free for many years. It appears that the primary effectors of tamoxifen activity are its active metabolites, rather than tamoxifen itself. Cytochrome P450 (CYP) enzymes, CYP2D6 in particular, play a major role in the metabolism of tamoxifen to active metabolites. More than 75 germline CYP2D6 variants have been identified. A test predicting lack of response to tamoxifen could supplement information used by clinicians and patients in treatment decision-making. For example, physicians and patients may opt to switch to an alternative therapy upfront.