Since its establishment in 1903, the National Wildlife Refuge System (NWRS) has grown to 635 units and 37 Wetland Management Districts in the United States and its territories. These units provide the seasonal habitats necessary for migratory waterfowl and other species to complete their annual life cycles. Habitat conversion and fragmentation, invasive species, pollution, and competition for water have stressed refuges for decades, but the interaction of climate change with these stressors presents the most recent, pervasive, and complex conservation challenge to the NWRS. Geographic isolation and small unit size compound the challenges of climate change, but a combined emphasis on species that refuges were established to conserve and on maintaining biological integrity, diversity, and environmental health provides the NWRS with substantial latitude to respond. Individual symptoms of climate change can be addressed at the refuge level, but the strategic response requires system-wide planning. A dynamic vision of the NWRS in a changing climate, an explicit national strategic plan to implement that vision, and an assessment of representation, redundancy, size, and total number of units in relation to conservation targets are the first steps toward adaptation. This adaptation must begin immediately and be built on more closely integrated research and management. Rigorous projections of possible futures are required to facilitate adaptation to change. Furthermore, the effective conservation footprint of the NWRS must be increased through land acquisition, creative partnerships, and educational programs in order for the NWRS to meet its legal mandate to maintain the biological integrity, diversity, and environmental health of the system and the species and ecosystems that it supports.