Vaccines have been successfully developed for the prevention of many viral diseases of humans. There are a number of other viral infections that cause diseases worthy of prevention but are more difficult to attack. These include herpes simplex, cytomegalovirus, and varicella zoster, all capable of persisting as latent infections. Human immunodeficiency virus (HIV) is perhaps the most difficult to control of all such virus diseases, and certainly the most important on a worldwide basis. This chapter reviews HIV as a prototype of those viruses that will probably defy conventional vaccines, and that challenges one to devise new approaches to immunization. It is discussed that an approach intracellular vaccination could render resistant to superinfection with HIV. Such approach involves the construction of an altered or avirulent strain of HIV, which would establish persistent infection and render infected cells resistant to superinfection with virulent HIV. Alternatively, uninfected cells could be stably transfected with a construct which encoded an RNA transcript capable of interfering with successful replication of HIV, such as an antisense tat sequence.