West Nile virus (WNV) infection of mosquitoes, birds, and vertebrates continues to spread in the Western Hemisphere. In humans, WNV infects the central nervous system and causes severe disease, primarily in the immunocompromised and elderly. In this review we discuss the mechanisms by which antibody controls WNV infection. Recent virologic, immunologic, and structural experiments have enhanced our understanding on how antibodies neutralize WNV and protect against disease. These advances have significant implications for the development of novel antibody-based therapies and targeted vaccines.