Mesenchymal stem/stromal cells (MSCs) are isolated from most post-natal tissues and are broadly reported to have similar immuno-phenotype, mesenchymal lineage-differentiation potential and bio-distribution in peri-vascular niches. Thus, several stromal substitutes of bone marrow mesenchymal stem cells (BMMSCs) are being considered for regenerative therapy. Wharton's jelly mesenchymal stem cells (WJMSCs) seem to be the most promising alternative because of easy donor accessibility, high proliferative capacity and greater sample to sample identity. Recent in vitro and in vivo evidences also support the usage of WJMSCs in tissue repair and regeneration. Key to these observations is secretion of trophic and immune regulatory factors, which aid repair, and resolution of injury. In order to extrapolate these results for clinical usage key questions that need to be addressed are: extrapolation of “allogeneic” transplantation ability of BMMSCs to WJMSCs, survival of allogeneic/xenogeneic WJMSCs in transplantation scenario and actual mechanisms of immune-modulation in an “inflammatory” setting. This review focuses on comparing the in vitro and in vivo studies on immune regulatory properties of WJMSCs and BMMSCs and speculates the usage of WJMSCs for immuno-modulation in a disease scenario. Despite commonalities, different tissue-derived MSCs are reported to have unique gene expression signatures. We would evaluate whether WJMSCs have unique inherent properties, owing to their bio-distribution and primitiveness, as compared to BMMSCs. Further, we debate whether these differences remain conserved on in vitro propagation and impact the immune properties of WJMSCs and speculate the pros and cons of using WJMSCs for allogeneic transplantation.