Given the interpatient biological heterogeneity and narrow therapeutic index of anticancer drugs, a practical method for personalizing cancer therapy is essential. Genotype-guided cancer therapy will provide an optimal approach to normalize systemic drug exposures, predict drug toxicities and/or enrich clinical efficacy. To date, over a dozen anticancer drugs approved by the US FDA require labeling regarding pharmacogenetic biomarkers (both germline and somatic). Many, but not all, have prospective, genotype-guided evidence-based data. Optimizing output from retrospective, prospective, cost-effectiveness and adaptive biomarker driven clinical trials will help drive the success of personalized cancer therapy. This review will discuss prospective genotype-guided clinical trials in patients with solid tumors and address barriers in clinical translation.