Human respiratory syncytial virus (HRSV) is a major respiratory viral pathogen causing moderate to severe upper and lower respiratory tract infections in all ages and across a wide range of patient populations. There are no currently approved vaccines and although a number of candidates are in various stages of development, the challenges are quite substantial. Presently, only a single agent is approved for HRSV prophylaxis, and therapeutic treatment options are severely limited and ineffective, particularly in the infant population. Antibody prophylaxis is restricted to use in populations at high-risk for hospitalization (infants under 35 weeks gestational age, infants with chronic lung disease, and infants with congenital heart disease). Aerosol administration of the guanosine analog ribavirin has been approved for the treatment of severe HRSV LRTI in both children and mechanically ventilated patients; however, there is still debate over its overall benefit and the risks associated with its use. Current therapy for those hospitalized due to HRSV is supportive. As such, there is great medical need for the development of agents to prevent and treat HRSV infections in all populations. Interestingly, many of the discovered agents against HRSV, both neutralizing antibodies and small molecules inhibitors, target the viral fusion (F) glycoprotein. In particular, three distinct chemical classes as exemplified by JNJ-2408068, VP-14637, and BMS-433771, which appear to block conformational intermediates of the viral fusion protein are reviewed.