Persistent viral infections causing serious diseases derive, primarily, from altered function of the immune system. Knowledge of the very complex composition and function of the innate and adaptive branches of the immune system is essential to understanding persistent infection. The best solution to the problem of persistent infection is by prevention using prophylactic vaccines. Hit and run viruses evade immune destruction by infecting new hosts and rarely persist. Hit and stay viruses evade immune control by sequestration, blockade of antigen presentation, cytokine escape, evasion of natural killer cell activities, escape from apoptosis, and antigenic change. Twelve prophylactic vaccines against hit and run agents exist, and there are only three vaccines against hit and stay viruses, all of which are of DNA composition. Several new vaccines against hit and stay viruses are feasible, but protective vaccines against RNA HIV and hepatitis C agents are highly unlikely, short of a major breakthrough. Therapeutic vaccines are very improbable without a magnitude of favorable new discoveries. In the meantime, antiviral chemotherapy, chemotherapy/prophylactic vaccination, and short interfering RNA silencing are worthy of intense investigation.