Current antiretroviral therapies suppress viremia to very low levels, but are ineffective in eliminating reservoirs of persistent HIV infection. Efforts toward the development of therapies aimed at HIV reservoirs are complicated by the evidence that HIV establishes persistent productive and nonproductive infection in a number of cell types and through a variety of mechanisms. Moreover, immunologically privileged sites such as the brain also act as HIV sanctuaries. To facilitate the advancement of our knowledge in this new area of research, in vitro models of HIV persistence in different cellular reservoirs have been developed, particularly in CD4+ T-cells that represent the largest pool of persistently infected cells in the body. Whereas each model presents clear advantages, they all share one common limitation: they are systems attempting to recapitulate extremely complex virus-cell interactions occurring in vivo, which we know very little about. Potentially conflicting results arising from different models may be difficult to interpret without validation with clinical samples. Addressing these issues, among others, merits careful consideration for the identification of valid targets and the design of effective strategies for therapy, which may increase the success of efforts toward HIV eradication.