With women in western countries spending nearly one-third of their lifetime beyond menopause and a substantial number of these women facing severe menopausal symptoms, the goal of sex hormone pharmacogenomics is to promote the safe use of hormone replacement therapy (HRT). This could be achieved by providing molecular predictors for the upfront stratification of women in need of relief from menopausal symptoms into those with a likely benefit from HRT and those with a contraindication due to an HRT-associated breast cancer risk or other adverse effects. An increasing knowledge base of sex hormone metabolism and its variability, HRT outcomes and breast cancer susceptibility, as well as emerging examples of pharmacogenomic predictors, underscore the potential relevance of genetic variations for HRT outcome. The genes responsible for the metabolism, signaling and action of sex hormones are at the heart of this research; however, pharmacogenomic investigation of their therapeutic effects due to the enormous complexity of the biological pathways involved is still in its infancy. This article discusses the current knowledge, challenges and potential future directions towards the goal of genotype-guided safer HRT use.