The selective estrogen receptor modulator tamoxifen has been used for more than three decades for the treatment, and more recently prevention, of breast cancer in women of all ages. The conversion of tamoxifen to active metabolites involves several cytochrome P450 (CYP) enzymes. CYP2D6 is the key enzyme responsible for the conversion of N-desmethyl tamoxifen to endoxifen. Single nucleotide polymorphisms in the CYP2D6 gene are not uncommon, and some alleles code for enzymes with reduced, null, or increased activity. Multiple studies suggest that women who carry one or two variant CYP2D6 alleles that encode enzymes with null or reduced activity may have an inferior breast cancer outcome when treated with tamoxifen in the adjuvant setting compared to women carrying two alleles encoding an enzyme with normal activity. Unfortunately, the data are not uniformly concordant, and definitive evidence that would change routine clinical practice is not yet available. CYP2D6 activity can also be reduced by concomitant use of drugs that inhibit the enzyme, including antidepressants used for psychiatric conditions or to relieve hot flashes, and these should be avoided in tamoxifen users whenever possible. Emerging data suggest that host factors may also predict interpatient variability in response to aromatase inhibitors.