The U.S. Fish and Wildlife Service (USFWS) is one of the oldest conservation organizations in the United States and is the only federal agency solely charged with conserving fish, wildlife, plants and their habitats. The agency leads numerous conservation initiatives, such as protecting and recovering endangered species, managing almost 600 wildlife refuges throughout all states and territories, enforcing federal wildlife laws, and regulating international wildlife trade. In the past, these activities have not accounted for climate change. The accelerating biodiversity crisis, in combination with climate uncertainty, adds to the existing complexity associated with responding to multiple anthropogenic stressors. Here we describe current practice and thinking related to climate uncertainty and management of USFWS resources. We focus on three agency domains which represent various conservation planning responsibilities: evaluating species to be listed as threatened or endangered, Habitat Conservation Plans for listed species, and land management techniques on wildlife refuges. Integrating climate considerations into agency planning documents is complex and we highlight effective current applications and suggest future improvements. Additionally, we identify outstanding research needs or management applications, and updates to existing policy that will aid in developing improved conservation strategies. Our synthesis contributes to ongoing efforts to incorporate climate uncertainty into conservation planning, natural resource management, and related policy revisions.