Twenty-five years after the onset of the HIV/AIDS epidemic in sub-Saharan Africa, precious lives continue to be lost. The consequences of the HIV/AIDS epidemic have been tragic indeed. In this article we review the response to HIV/AIDS in sub-Saharan Africa. We argue that the disease spread rapidly in this region because many of the policies and prevention efforts were initiated rather late and were half-hearted at best. Many governments on the continent and key individuals continue to respond to the AIDS pandemic indecisively. This notwithstanding, we show that there is hope for stemming the tide, as illustrated by the case studies from Uganda and Senegal. We conclude the article by pointing out the need for researchers and policymakers to incorporate the deep-rooted reverential belief about spiritual forces when formulating strategies for changing sexual behaviors in sub-Saharan African.