Since the isolation of respiratory syncytial virus (RSV) in 1956, its significance as an important human pathogen in infants, the elderly and the immunocompromised has been established. Many important mechanisms contributing to RSV infection, replication and disease pathogenesis have been uncovered; however, there is still insufficient knowledge in these and related areas, which must be addressed to facilitate the development of safe and effective vaccines and therapeutic treatments. A better understanding of the molecular pathogenesis of RSV infection, particularly the host-cell response and transcription profiles to RSV infection, is required to advance disease intervention strategies. Substantial information is accumulating regarding how RSV proteins modulate molecular signaling and regulation of cytokine and chemokine responses to infection, molecular signals regulating programmed cell death, and innate and adaptive immune responses to infection. This review discusses RSV manipulation of the host response to infection and related disease pathogenesis.