<p>Antiretroviral therapy (ART) has markedly improved the life-expectancy of people living with HIV. However, during both HIV infection of humans and simian immunodeficiency virus infection of macaques, virus replication almost invariably rebounds upon ART interruption, due to the long-term persistency of a pool of latently infected cells harbouring integrated, replication-competent virus (known as the virus reservoir). Solving this ‘HIV reservoir problem’ is the key to achieving a cure (or at least a persistent remission) for HIV infection. Here, we summarize the key scientific evidence supporting the hypothesis that host immune responses, including those mediated by CD8⁺ T cells, B cells, antibodies and innate immune cells, affect the size, clonality, and cellular, tissue and organ distribution of the HIV reservoir. Importantly, we believe that any solution to the ‘reservoir problem’ must address not only the multifaceted interactions between HIV and the host immune system, but also the complex interplay between the immunobiology of memory CD4⁺ T helper cells (which form the main virus reservoir) and the molecular mechanisms that regulate HIV latency and reactivation. These concepts provide the rationale to develop new, immune-based approaches to ‘cure’ HIV infection; we review recent efforts to develop such therapies and their efficacy (or lack thereof) in disrupting the establishment and/or persistence of the virus reservoir in preclinical animal models and human clinical trials.</p>