Infection with human immunodeficiency virus (HIV) disrupts the balance among γδ T cell subsets, with increasing Vδ1+ cells and substantial depletion of circulating Vδ2+ cells. Depletion is an indirect effect of HIV in CD4-negative Vδ2 cells, but is specific for phosphoantigen-responsive subpopulations identified by the Vγ2-Jγ1.2 (also called Vγ9-JγP) T cell receptor rearrangement. The extent of cell loss and recovery is related closely to clinical status, with highest levels of functional Vδ2 cells present in virus controllers (undetectable viremia in the absence of antiretroviral therapy). We review the mechanisms and clinical consequences for Vδ2 cell depletion in HIV disease. We address the question of whether HIV-mediated Vδ2 cell depletion, despite being an indirect effect of infection, is an important part of the immune evasion strategy for this virus. The important roles for Vδ2 cells, as effectors and immune regulators, identify key mechanisms affected by HIV and show the strong relationships between Vδ2 cell loss and immunodeficiency disease. This field is moving toward immune therapies based on targeting Vδ2 cells and we now have clear goals and expectations to guide interventional clinical trials.