Despite recent advances in hormonal therapy for breast cancer, tamoxifen remains a major therapeutic option, with indications ranging from primary prevention to metastatic disease. Understanding the variation in response to tamoxifen may significantly improve our ability to personalize cancer care and maximize therapeutic efficacy. One area of particular interest is the impact of cytochrome P450 CYP2D6 genetic polymorphisms on tamoxifen metabolism. Tamoxifen is considered a prodrug, whose efficacy may be dependent on active metabolites, including endoxifen. Patients with reduced CYP2D6 enzymatic activity tend to have lower endoxifen levels, but clinical relevance of reduced endoxifen levels remains to be determined. Several small to moderately sized retrospective studies have suggested an intriguing association between poor metabolizer status and increased disease recurrence. However, these data are limited by sample size and methodologic challenges, including the inability to adjust for major prognostic and confounding factors. Several subsequent studies have failed to find an association or found improved outcomes among reduced CYP2D6 metabolizers. Therefore, current findings are conflicting and should be considered preliminary. Nevertheless, the CYP2D6 test is commercially available, making clinical use possible even as evidence in this area is still evolving. More definitive clinical research is needed before routine CYP2D6 testing can be recommended and considered standard of care. Anticipated data from retrospective analysis of large adjuvant randomized trials of tamoxifen should help address the clinical utility of CYP2D6 testing.