Despite effective antiretroviral therapy (ART), HIV-infected individuals have residual chronic immune activation that contributes to the pathogenesis of HIV infection. This immune system dysregulation is a pathogenic state manifested by very low naïve T-cell numbers and increased terminally differentiated effector cells that generate excessive proinflammatory cytokines with limited functionality. Immune exhaustion leaves an individual at risk for accelerated aging-related diseases, including renal dysfunction, atherosclerosis, diabetes mellitus, and osteoporosis. We highlight research that clarifies the role of HIV, ART, and other factors that contribute to the development of these diseases among HIV-infected persons. © 2014 Elsevier Inc.