Respiratory syncytial virus (RSV) is an important respiratory pathogen for which vaccine development has been thwarted by the legacy of vaccine-enhanced illness. A formalin-inactivated, alum-precipitated, whole virus vaccine did not protect children from infection and was associated with severe illness. Clues from clinical studies of RSV and vaccine-induced atypical measles illness suggest that an aberrant CD4+ lymphocyte response occurred in vaccinees. There is a growing body of evidence from murine models that show vaccine formulations can selectively activate different populations of CD4+ T helper lymphocytes that produce distinct cytokine expression patterns. The cytokine milieu in turn can influence the composition of the immune response and thereby impact the efficiency of virus clearance, type of pathology, and magnitude of illness. Major priorities of current vaccine development are to define the optimal combination of T lymphocyte subsets to safely clear RSV and to learn ways to modulate the composition of the immune response to vaccine antigens.