Impressive advances have been made in the treatment and management of HIV-1 infected individuals. Combination antiretroviral therapy (cART) has turned HIV-1 infection from an almost invariable deadly infectious disease, to a lifelong manageable infectious disease. However, a cure or vaccine has not been forthcoming. A major problem in HIV-1 infection is the persistent and latently infected cellular and tissue reservoirs. One of these reservoirs is the Gut Associated Lymphoid tissue (GALT), which has been the research focus of our group. Our group and others have shown that HIV-1 evolves differently in different parts of the gastro intestinal tract, which also appears to affect the development of antiretroviral drug resistance. The GALT is not the only reservoir. HIV-1 continues to persist and evolve in various other cell and tissue reservoirs despite intense and apparent successful antiretroviral therapy. Moreover, drug resistance mutations remain prevalent under therapy and successful viral suppression. In addition to finding a vaccine, the research on combating and eradicating the HIV-1 viral reservoirs has also been an important focus of HIV-1 cure strategies. We will discuss some of the research findings on reservoirs in the context of some of the HIV-1 cure approaches.