Palivizumab (PZ) is the only monoclonal antibody in human use against an infectious disease. PZ is a humanized monoclonal antibody that recognizes the fusion protein of respiratory syncytial virus (RSV). PZ prophylaxis reduces the likelihood of hospitalization for young children at risk for severe RSV infections. The quasispecies nature of RNA viruses allows rapid emergence of viruses with a selective advantage. A PZ resistant virus was selected by passage of RSV in the presence of PZ in cell culture. The cell culture-derived virus was completely resistant to PZ prophylaxis in cotton rats. The increasing use of PZ, and in particular, the use of PZ in immunosuppressed patients, provide opportunities for resistant viruses to emerge. Whether such viruses will appear and be of clinical significance for humans is unknown. Preclinical studies in cotton rats predicted the efficacy of PZ in humans; these results suggest that if PZ resistant viruses arise in humans, PZ prophylaxis may be ineffective.