The human microbiome is constituted by an extensive network of organisms that lie at the host/environment interface and transduce signals that play vital roles in human health and disease across the lifespan. Frailty is a critical aging-related syndrome marked by diminished physiological reserve and heightened vulnerability to stress, predictive of major adverse clinical outcomes including death. While recent studies suggest the microbiome may impact key pathways critical to frailty pathophysiology, direct evaluation of the microbiome-frailty relationship remains limited. In this article, we review the complex interplay of biological, behavioral, and environmental factors that may influence shifts in gut microbiome composition and function in aging populations and the putative implications of such shifts for progression to frailty. We discuss HIV infection as a key prototype for elucidating the complex pathways via which the microbiome may precipitate frailty. Finally, we review considerations for future research efforts.