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Extensive efforts have been engaged over the past two decades to characterize and attempt to eradicate a pool of long-lived, virus-infected cells in patients living with human immunodeficiency virus (HIV). This pool of cells, which persists in HIV-infected patients, consists largely of infected CD4+ T lymphocytes that enter and maintain a resting or quiescent memory state in which viral expression is repressed. The longevity of this pool of cells, referred to as the latent reservoir, precludes the possibility of patient withdrawal from potent anti-retroviral therapy (ART) without a predictable rebound of blood born virus despite long-term administration of ART. This circumstance mandates that the vast majority of HIV-infected individuals remain on ART indefinitely. There are compelling reasons to pursue ablation of the latent reservoir since it serves as a persistent source from which viremia ensues upon withdrawal of ART. A means to eradicate this reservoir would be regarded as tantamount to a cure of the infection and relieve patients from life-long administration of ART. This review outlines the mechanisms of latent reservoir formation and its sustenance. It presents circumstances of individuals who are naturally refractory to viremia without the necessity of ART or have been treated to become so. Both of these circumstances may serve as mechanistic models toward the design and implementation of a sterilizing cure. Finally, a number of molecular-based strategies are discussed which are directed toward the complete and sustained suppression of virus expression and/or eradication of the latent reservoir which still remains an elusive goal.