Although live‐attenuated human immunodeficiency virus‐1 (HIV) vaccines may never be used clinically, these vaccines have provided the most durable protection from intravenous (IV) challenge in the simian immunodeficiency virus (SIV)/rhesus macaque model. Systemic infection with virulence attenuated‐simian–human immunodeficiency virus (SHIV) 89.6 provides protection against vaginal SIV challenge. This paper reviews the findings related to the innate and adaptive immune responses and the role of inflammation associated with protection in the SHIV 89.6/SIVmac239 model. By an as yet undefined mechanism, most monkeys vaccinated with live‐attenuated SHIV 89.6 mounted effective anti‐viral CD8+ T cell responses while avoiding the self‐destructive inflammatory cycle found in the lymphoid tissues of unprotected and unvaccinated monkeys.