The United States has held strong national interest in Panama since the 1840s. This interest was demonstrated by the building of the Panama Canal, its ensuing operation, and numerous military interventions into Panama concluding with Operation Just Cause in 1989. Control of the canal formally passed to Panama and the American military presence ended in 1999. By the 1977 Panama Canal Neutrality Treaty, the United States retained the right to intervene unilaterally if the canal or its neutral operation is threatened. Will the United States consider the Panama Canal a vital interest in the twenty-first century? This monograph summarizes the United States historical involvement with the canal. Current economic, military and intangible American interests in the canal are analyzed. The most likely threats to the canal or American access to it are evaluated. These findings are considered against the backdrop of theories put forward by Alfred Thayer Mahan, Julian S. Corbett and Thucydides. The monograph finds American economic and military interests in the canal have significantly depreciated over time. However, United States policy calls for global access and freedom of navigation to protect its vital interests. These principles combined with national prestige and honor will require the United States to consider the Panama Canal a vital interest in the twenty-first century.