Respiratory syncytial virus (RSV) is a clinically significant cause of respiratory tract disease, especially among high-risk infants and immunocompromised and elderly adults. Despite the burden of disease, there is no licensed prophylactic RSV vaccine. The initial efforts to develop an RSV vaccine involved formalin-inactivated virus preparations that unexpectedly caused vaccine-enhanced disease in clinical trials in RSV-naive children. Over the last 40 years, cautious and deliberate progress has been made toward RSV vaccine development using various experimental approaches, including live attenuated strains and vector-based and viral protein subunit/DNA-based candidates. The scientific rationale, preclinical testing, and clinical development of each of these approaches are reviewed.