Advancements and innovation in in vitro diagnostic device (IVD) development are important for the success of personalized medicine. This is highlighted by the dramatic increase in the number of biomarker-targeted drug development programs since the first companion diagnostic and corresponding drug were approved in 1998. An overview of the current regulatory landscape for molecular diagnostics for oncology applications will be provided, with a focus on companion diagnostics and next generation sequencing (NGS)-based IVDs. Key issues and strategies impacting the regulatory framework for NGS assays for cancer indications will be discussed, and recent FDA clearances and approvals of diagnostic devices will serve as examples.