The Veterans Aging Cohort Study Index (VACS Index) is an index comprised of routine clinical laboratory tests that accurately and generalizably predicts all-cause mortality among those living with and without HIV infection. Increasing evidence supports its use as a measure of physiologic frailty among those aging with HIV because of its associations with frailty related outcomes including mortality, hospitalization, fragility fractures, serious falls, pneumonia, cognitive decline, delirium, and functional decline. In this review, we explore the evidence supporting the validity (construct, correlative, and predictive), responsiveness, and feasibility of the VACS Index as an early indicator of physiologic frailty. We also consider its limitations.