Aging is associated with declines in physical function that can be influenced by many factors, including HIV. These limitations may manifest as increased vulnerability to stressors, or frailty. Functional limitations and frailty can be used to guide clinical decisions, protect people from harm, and avoid strategies that are not likely to provide benefits. Such limitations could also serve as clinically relevant endpoints for some clinical trials. Interventions should ideally focus on early impairments that begin to occur in midlife, well before an individual becomes frail or experiences disabilities. Overall, physical activity is safe and effective in improving physical function, and counseling about physical activity should be a routine component of HIV care to increase the lifespan and healthspan of individuals with HIV. There are some promising pharmaceutical options, but more research is needed to determine the safety and long-term efficacy. This article summarizes an International Antiviral Society-USA (IAS-USA) webinar presented by Kristine M. Erlandson, MD, MS, on July 24, 2020. This webinar is available on demand at https://www.iasusa.org/courses/on-demand-webinar-2020-erlandson/.