Tamoxifen is a selective estrogen-receptor modulator that is commonly utilized in the treatment and prevention of endocrine receptor-positive breast cancer. Ultimate conversion of the parent drug by the enzyme CYP2D6 to the active metabolite, endoxifen, is required for tamoxifen to exert its anticancer effects. CYP2D6 exists in varying concentrations across individuals due, in part, to genetic variation. Lower concentrations of endoxifen have been associated with inferior breast cancer outcomes in numerous retrospective trials. In an effort to increase the endoxifen concentrations, three prospective trials have assessed different methods of increasing tamoxifen dose based on patient CYP2D6 genotypes. All three demonstrated the ability to increase endoxifen concentrations using tamoxifen at a dose of 30 or 40 mg daily. These positive findings support future investigations to determine, not only the clinical benefit of genotype-guided therapy, but also the optimal dose needed for individual patients.