Abstract: Polygenic risk scores ("PRSs") provide genome-wide estimates of disease risk by aggregating the effects of thousands of genetic variants across the genome. These scores are the subject of immense scientific interest as research tools and more recently as clinical instruments that may allow for physicians to stratify populations based on underlying genetic predisposition, or to tailor therapeutic interventions based on their needs and likelihood of benefit. While their status as research tools has long-been recognized, these scores are no undergoing clinical trials, increasing the evidence base for their use in clinical settings. These scores have also entered the consumer market, prompting industry experts to call on greater regulatory insight. However, in part due to the speed of these developments, the legal literature has failed to comprehensively assess the nature of these scores, and whether they differ fundamentally from previous forms of genetic scoring which have been regulated by the complex (yet familiar) regulatory regime for genetic testing. This Article fills this gap in the literature by comparing the state-of-the-art methodological tools used to generate these scores with familiar forms of genetic testing (e.g., IVDs and LDTs). We identify four dimensions that make PRS distinct from previous genetic testing regimes -- (1) the underlying method of assessing genetic risk; (2) an evolving evidence base; (3) lack of consensus on methodology; (4) diversity of device functions that PRSs may apply to. Taking these insights in concert, this Article also offers several principles for regulatory design as it relates to PRSs. These principles include the need for a unified approach across all devices that incorporate PRSs, the value of taking a risk-based framework, and drawing lessons from AI/ML regulation. Ultimately, while the existing risk-based device framework will serve as a stopgap for the most clinically impactful use cases (and those that pose the most risk to patients and the public), PRSs and other novel technologies may evince the need for updates to the authorities granted to the existing regulatory regime to balance scientific innovation with the public interest.