Adverse drug reactions, including an unexpected lack of efficacy and toxicity, are common and costly, being the fourth leading cause of death among hospitalized patients [1]. For most drugs in clinical use, there exists marked interpatient variability in drug responsiveness, often related to pharmacogenetic (PGx) differences. This holds true for breast cancer patients taking tamoxifen, the most commonly used adjuvant antiestrogen therapy. These patients are prescribed a single 20 mg/day dose of tamoxifen, for at least 5 years, with the hope that this ‘one-size-fits-all’ strategy will be effective at preventing recurrence. However, we recently observed that endoxifen levels in patients on the same dose can vary by tenfold, and nearly 25% of these patients are not achieving optimal benefit [2]. Tamoxifen is a prodrug that undergoes hepatic metabolism, predominantly by the CYP450 enzyme CYP2D6, to form its active metabolite known as endoxifen [3]. Endoxifen is 50–100-times more effective at blocking the estrogen receptor compared with tamoxifen; therefore, attaining and maintaining sufficient levels of endoxifen is likely to be key to therapeutic success. Recently, Murdter et al. demonstrated that endoxifen concentrations higher than 14 nM are required for 90% estrogen receptor occupancy in vitro [4]. Additionally, Madlensky et al. observed that patients in the lowest quintile of endoxifen levels (<15 nM) had the highest recurrence rates [5]. Using a breast cancer tumorbearing mouse model, we showed that endoxifen levels below 15 nM result in suboptimal tumor growth inhibition [6]. Taken together, these studies suggest that a threshold of endoxifen is required for optimal therapeutic benefit from tamoxifen. This raises two important clinical problems: how do we identify patients who are at risk of subtherapeutic benefit; and how do we ensure all patients achieve therapeutic endoxifen