The assembly of the N-terminus heptad repeats of the respiratory syncytial virus (RSV) F protein into a trimeric complex that associates with the C-terminus heptad repeats to form a six-helix bundle is a critical step in the process of virus-host fusion and represents an intramolecular protein-protein interaction. Screening campaigns using replicating virus assays have identified several structurally distinct but mechanistically similar chemotypes that interfere with RSV fusion by disrupting the function of the F protein six-helix bundle. This chapter summarizes structure-activity relationships and mechanistic insights associated with the most prominent RSV fusion inhibitors and the key issues in the development of potential clinical candidates.