Summary: Comprehensive genomic profiling is expected to revolutionize cancer therapy. In this Prospective, we present the prevalence of mutations and copy-number alterations with predictive associations across solid tumors at different levels of stringency for gene–drug targetability. More than 90% of The Cancer Genome Atlas samples have potentially targetable alterations, the majority with multiple events, illustrating the challenges for treatment prioritization given the complexity of the genomic landscape. Nearly 80% of the variants in rarely mutated oncogenes are of uncertain functional significance, reflecting the gap in our understanding of the relevance of many alterations potentially linked to therapeutic actions. Access to targeted agents in early clinical trials could affect treatment decision in 75% of patients with cancer. Prospective implementation of large-scale molecular profiling and standardized reports of predictive biomarkers are fundamental steps for making precision cancer medicine a reality. Cancer Discov; 5(2); 118–23. ©2015 AACR.