Respiratory syncytial virus (RSV) causes significant morbidity in very young children, preterm infants with and without chronic lung disease, and children with hemodynamically significant congenital heart disease. In the absence of a safe and effective vaccine, alternative means of protecting high-risk infants and young children from serious RSV illness have been studied. Clinical observations and animal model data over the past 30 years suggested that RSV immunoglobulin G (IgG) neutralizing antibodies might offer protection from severe RSV lower respiratory tract disease. Transfer of adequate amounts of IgG to the fetus does not occur efficiently until the third trimester of pregnancy, which helps to explain why premature infants are at high risk of serious RSV illness. Efforts shifted toward the prophylactic monthly administration of standard immunoglobulins and, later, of RSV-enriched immunoglobulin in selected high-risk infants and young children. Although this approach proved effective, RSV-enriched immune globulin was not suitable for all patients and administration was labor intensive. The development of palivizumab, a monoclonal antibody that can bind to a specific antigenic site on the virus and prevent cell-to-cell spread of infection has since become the mainstay of RSV illness prevention in preterm infants and those with significant congenital heart disease. Palivizumab, the only monoclonal antibody approved for the prevention of RSV lower respiratory tract disease must be administered monthly throughout the RSV season and does not always prevent serious RSV illness. Further research to develop more effective and less labor-intensive immunoprophylactic agents is ongoing.