The technological possibilities and future public health importance of metagenomic sequencing have received extensive attention, but there has been little discussion about the policy and regulatory issues that need to be addressed if metagenomic sequencing is adopted as a key technology for biosurveillance. In this article, we introduce metagenomic monitoring as a possible path to eventually replacing current infectious disease monitoring models. Many key enablers are technological, whereas others are not. We therefore highlight key policy challenges and implementation questions that need to be addressed for “widespread metagenomic monitoring” to be possible. Policymakers must address pitfalls like fragmentation of the technological base, private capture of benefits, privacy concerns, the usefulness of the system during nonpandemic times, and how the future systems will enable better response. If these challenges are addressed, the technological and public health promise of metagenomic sequencing can be realized.

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