The aim of precision medicine is to select the best treatment option for each patient at the appropriate time in the natural history of the disease, based on understanding the molecular makeup of the tumor, with the ultimate objective of improving patient survival and quality of life. To achieve it, we must identify functionally distinct subtypes of cancers and, critically, have multiple therapy options available to match to these functional subtypes. As a result of the development of better and less costly next-generation sequencing assays, we can now interrogate the cancer genome, enabling us to use the DNA sequence itself for biomarker studies in drug development. The success of DNA-based biomarkers requires analytical validation and careful clinical qualification in prospective clinical trials. In this article, we review some of the challenges the scientific community is facing as a consequence of this sequencing revolution: reclassifying cancers based on biologic/phenotypic clusters relevant to clinical decision making; adapting how we conduct clinical trials; and adjusting our frameworks for regulatory approvals of biomarker technologies and drugs. Ultimately, we must ensure that this revolution can be safely implemented into routine clinical practice and benefit patients.