The vast number of African non-human primates species that are naturally infected with the simian immunodeficiency viruses ( SIV) but have not shown any signs of lentivirus associated disease as compared to the Asian non-human primate species that do not demonstrate any detectable signs of lentiviral infection but who upon experimental infection with select SIV isolates from the African species develop clinical signs and laboratory based findings similar to human HIV-1 infection provide a powerful model to define virus-host relationships. It is our belief that unraveling those differences which are specifically associated with disease resistance and/or disease susceptibility culled out from those that are species specific differences unrelated to disease outcome may provide some important insights which maybe fruitful for the formulation of vaccine strategies. The purpose of this chapter is to provide the reader with a summary of the findings from our laboratory from the past decade using the naturally SIV infected sooty mangabey model aimed at ferreting out some of these differences. Some very important paradoxes exist with this naturally infected lentivirus model. Thus, it is difficult to determine why these species demonstrate highly effective immune responses but yet maintain very high viral loads. Why do these naturally SIV infected species not demonstrate the plethora of clinical symptoms ascribed to select proteins of the SIV such as 'tat', 'nef', and other viral proteins as do the rhesus macaques and humans to HIV? Most of the targets of such proteins are highly conserved and yet no detectable pathology? We submit that the naturally infected species has evolved over time with a highly regulated immune system (a perfect host/parasite relationship) that is sufficient to prevent pathology and not in the order to exhaust the immune system. In addition, the quality of the anti-viral immune response is of interest. Thus, the mangabeys demonstrate a clear skew in their cytokine based immune response towards a predominantly TH2 bias which we believe is the reason why this species of mangabeys among the many studied, is perhaps is the only species that is susceptible to M. leprae infection (see Dr. B. Gormus's chapter). Some of our working hypotheses that are aimed to provide explanations for some of these paradoxes are provided herein.