Signals mediating in vivo BMSC activation in the context of infectious challenge and their subsequent effects on MSC-mediated immunomodulation remain largely undefined. Infectious challenge is associated with induction in pathogen- and sterile-induced soluble factors that may influence BMSC activation and subsequent immunomodulation. As infectious burden increases, so too do associated inflammatory and damage burdens at the site of infection. By nature of their multipotency, BMSCs may possess plasticity in their immunomodulatory effects to respond to the changing microenvironment at the site of infectious challenge. Specifically, the inflammatory and damage milieu may instruct or “license” BMSC activation and function specific to the microenvironment in which BMSCs reside or to which they migrate as a consequence of infection. Further investigation is needed to define these signals within the in vivo microenvironment as well as their effects on MSC activation in addition to resultant immunomodulatory effects of MSCs on host immunity.