In light of the article "Understanding CYP2D6 and Its Role in Tamoxifen Metabolism" (Smith, 2013), we feel it imperative to comment on the recent, unexpected approval by the U.S. Food and Drug Administration (2013) of the selective serotonin reuptake inhibitor paroxetine as a nonhormonal treatment for menopausal hot flashes. Paroxetine is a strong inhibitor of CYP2D6, the same enzyme system that converts tamoxifen to its active form, endoxifen. Thus, women receiving tamoxifen therapy for hormone-positive breast cancer should be informed of the risk of reducing tamoxifen efficacy with concomitant use of paroxetine to treat their tamoxifen-induced hot flashes (Kaplan & Mahon, 2013). National Comprehensive Cancer Network (2013) guidelines currently recommend against coadministration of strong inhibitors of CYP2D6 with tamoxifen. In addition, a systematic, evidence-based review of interventions to manage hot flashes in women with breast cancer and men with prostate cancer found only two agents likely to be effective, the serotonin-norepinephrine reuptake inhibitor venlafaxine, and gabapentin. Paroxetine was among the many interventions ranked evidence not established (Kaplan et al., 2011).