On-demand gene synthesis is a growing industry that has democratized access to customized synthetic DNA and RNA products used in biological research. This emerging technology may present risks that could allow nefarious actors to obtain sequences of dangerous organisms or novel-engineered pathogens to construct a biological weapon. Securing nucleic acid synthesis has emerged as a federal policy priority. The 2022 National Biodefense Strategy and Implementation Plan for Countering Biological Threats, Enhancing Pandemic Preparedness, and Achieving Global Health Security issued by the White House recommends enhancing screening of nucleic acid synthesis orders and developing systems for identifying and reporting suspicious orders. Executive Order 14110 tasks the White House Office of Science and Technology Policy with establishing a framework “to encourage providers of synthetic nucleic acid sequences to implement comprehensive, scalable, and verifiable synthetic nucleic acid procurement screening mechanisms, including standards and recommended incentives” (Executive Order 14110, 2023, p. 75201). Customers who receive federal funding will be required to obtain synthetic gene products only from providers who adhere to the new framework. The Framework for Nucleic Acid Synthesis Screening describes basic responsibilities of synthetic sequence providers. In this report, we provide recommendations for securing commercial nucleic acid synthesis services against misuse. We reviewed U.S. government screening guidelines, the new government framework, synthetic biology industry consortium requirements, state legislative proposals, and the scientific literature to answer the following research questions: • What is the current state of commercial gene synthesis screening? • How should providers determine whether an order is suspicious? • How can providers or third parties ensure that suspicious orders split across providers will be detected? • How should information about suspicious orders be relayed to law enforcement? • How should providers’ conformity with screening rules be verified? Implementation of the recommendations described in this report would satisfy the requirements of several components of Executive Order 14110, helping to secure the synthetic nucleic acid industry against its products being misused to create a dangerous biological weapon. The recommendations first propose an overall screening workflow for providers to implement, followed by recommendations to establish a database to log information about orders, implement customer screening, communicate with law enforcement, and assess providers’ conformity with the screening framework. The intended audience for this report consists of U.S. government officials and their agencies tasked with responding to Executive Order 14110 section 4.4(b), synthetic biology industry stakeholders, and synthetic nucleic acid customers.