Many targeted therapies-and, more recently, immunotherapies-have been approved by the U.S. Food and Drug Administration (FDA) with companion diagnostic tests. Next-generation sequencing (NGS) platforms are now approved to screen for many of these abnormalities, and they are increasingly being applied to guide therapeutic decision-making outside of these intended uses. The results provided by NGS testing can vary significantly based on the exact test performed and the analysis of the sequencing data. Given the complexities associated with interpreting NGS test results and acting on them, academic and community molecular tumor boards have been developed to provide multidisciplinary expertise for this endeavor. NGS test results may identify FDA-approved therapies, guide clinical trial recommendations, or prompt consideration of expanded access to investigational agents or off-label use of therapies approved for other indications. Many clinical trials now include NGS testing to assign treatments to patients based on the molecular profiles of their tumors. Although NGS testing may eventually help realize the development of individualized treatment regimens based on combinations of targeted therapies, the use of unproven and nonapproved combinations can be toxic and expensive. Given the increasing reliance on genetic biomarkers to guide therapeutic recommendations for FDA-approved therapies or enrollment into clinical trials, NGS will remain an integral part of the evolving medical oncology practice.