The HIV pandemic represents a new challenge to biomedical research. What began as a handful of recognized cases among homosexual men in the US has become a global pandemic of such proportions that it clearly ranks as one of the most destructive viral scourges in history. In the past few years new treatments and drugs have been developed and tested, but the development of a new generation of therapies remains a major priority, because of the lack of chemotherapeutic drugs or vaccines that show long-term efficacy in vivo. Recently, gene therapeutic strategies for the treatment of patients with HIV infection have received increased attention because they are able to offer the possibility of simultaneously targeting multiple sites in the HIV genome, thereby minimizing the production of resistant virus. Recombinant genes for gene therapy can be classified as expressing interfering proteins (intracellular antibodies, dominant negative proteins) or interfering RNAs (antisense RNAs, ribozymes, RNA decoys). The latter group offers the advantage of avoiding the stimulation of host immune response which might progressively decrease the efficacy of proteins. The stumbling block to achieving lasting antiviral effects is still represented by the lack of efficient gene transfer techniques capable of generating persistent transgene expression and a high number of transduced cells relative to untransduced cells. Novel delivery vectors, such as lentiviruses, might overcome some of these shortcomings. The use of recombinant genes to generate immunity is a very promising concept that is rapidly expanding. Since the immune system can significantly amplify the response to tiny amounts of antigen, DNA vaccines can indeed be delivered by exploiting traditional gene therapy approaches without the need of high transduction efficiency.