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Marine protected areas (MPAs) are a key tool for achieving goals for biodiversity conservation and human well-being, including improving climate resilience and equitable access to nature. At a national level, they are central components in the U.S. commitment to conserve at least 30% of U.S. waters by 2030. By definition, the primary goal of an MPA is the long-term conservation of nature; however, not all MPAs provide the same ecological and social benefits. A U.S. system of MPAs that is equitable, well-managed, representative and connected, and includes areas at a level of protection that can deliver desired outcomes is best positioned to support national goals. We used a new MPA framework, The MPA Guide, to assess the level of protection and stage of establishment of the 50 largest U.S. MPAs, which make up 99.7% of the total U.S. MPA area (3.19 million km²). Over 96% of this area, including 99% of that which is fully or highly protected against extractive or destructive human activities, is in the central Pacific ocean. Total MPA area in other regions is sparse – only 1.9% of the U.S. ocean excluding the central Pacific is protected in any kind of MPA (120,976 km²). Over three quarters of the non-central Pacific MPA area is lightly or minimally protected against extractive or destructive human activities. These results highlight an urgent need to improve the quality, quantity, and representativeness of MPA protection in U.S. waters to bring benefits to human and marine communities. We identify and review the state of the science, including focal areas for achieving desired MPA outcomes and lessons learned from places where sound ecological and social design principles come together in MPAs that are set up to achieve national goals for equity, climate resilience, and biodiversity conservation. We recommend key opportunities for action specific to the U.S. context, including increasing funding, research, equity, and protection level for new and existing U.S. MPAs.