Mesenchymal stem cells (MSCs) were originally defined by their capacity to differentiate into various connective tissue lineages as well as support hematopoiesis in vitro via the production of various cytokines, chemokines, and adhesion molecules [1, 2]. During the past decade, MSCs have been shown to exhibit angiogenic, trophic, anti-inflammatory, and immunomodulatory activity using a variety of experimental paradigms [3–6]. Together with their easy availability and amenability to large-scale expansion ex vivo, these properties have propelled MSC-based therapies to the forefront of regenerative medicine and immune regulatory cell therapy. Currently, MSCs from a variety of tissue sources are being evaluated in over 200 clinical trials for the treatment of a diverse array of disease indications. Completed Phase I and II clinical trials have reported statistically significant benefits in patients with steroid-resistant graft versus host disease [7], severe systemic lupus erythematosus [8], complex perianal fistulas [9], and ischemic cardiomyopathy [10]. However, not all trials have met their primary endpoint of efficacy and while many factors contribute to suboptimal patient outcomes, key among them are the molecular mechanisms that govern MSC engraftment, homing, and biodistribution in vivo. Indeed, despite rapid progress in describing the therapeutic potency of MSCs in experimental animal models of disease, progress in understanding their biodistribution and mechanism of action in vivo has been slow to develop. For example, robust methodologies to track the fate of MSCs in vivo are critical toward establishing their tissue tropism, duration of engraftment, and rates of clearance. In addition, the identification of endogenous factors that function as chemoattractants and repellents also plays critical roles in directing transplanted cells to sites of tissue injury. Moreover, a clearer understanding of the signaling axes that regulate MSC trafficking in vivo would provide a means to direct cells to specific tissue and organs, thereby increasing overall efficacy of MSC-based therapies. The latter may also provide a means to mobilize endogenous MSCs and enhance their regenerative and immune regulatory properties. Finally, cellular crosstalk and cell-to-cell interactions also likely affect the biodistribution and survival of exogenously administered MSCs, but scant information exists regarding these processes in vivo. In fact, it is a subject of debate whether MSCs localize to tissue due to passive entrapment in small vessels, particularly in lung, or if cells employ active mechanisms similar to leukocytes to home to specific tissues. Therefore, continued study into the mechanism that regulates trafficking