Cytomegalovirus (CMV) infection elicits a potent immune response that includes the stimulation of antibodies with neutralizing activity. Recent studies have focused on elucidating the role of neutralizing antibodies in protecting against CMV infection and disease and characterizing viral antigens against which neutralizing antibodies are directed. Here, we provide a synthesis of recent data regarding the role of neutralizing antibodies in protection against CMV infection/disease. We consider the role of humoral immunity in the context of the global CMV-specific immune response, and the implications that recent findings have for vaccine and antibody-based therapy design.