The Human mesenchymal stromal/stem cells (MSCs) have been isolated from various tissue sources. Yet, the lack of a distinctive marker for identifying in vivo MSCs in their tissue niche has hampered the MSC's in vivo behavior tracking and compared that to the in vitro expanded cultures. In this review, we present a comprehensive report on MSCs history, isolation from assorted tissue sources, classification, long-term cultures for comprehensively characterized MSCs, immunomodulation, regenerative medical applications, iMSCs as a novel source of patient-specific iPSCs and scaleup strategies for translational applications. We have emphasized on prenatal tissue-derived MSCs and iMSCs derived from hiPSCs as an effective alternative to adult MSCs. We also highlight the urgent requirement to revisit the initial criteria laid down by International Society for Cellular Therapy (ISCT) and propose more stringent criteria to define, identify and exclusively characterize the MSCs derived from various tissue sources using advanced molecular tools; also more international workshops are necessary for delineating unique features of MSCs. Unless the proposed goal is achieved, it is extremely difficult to realize the full potential of MSCs in translational applications. Although numerous patients have been tested with MSCs to date, no immediate adverse outcomes or infusion-related toxicity has been reported, suggesting MSCs infusion to be safe. However, rare adverse event and late complications of the treatment may be detected in large cohorts of patients with long-term follow-up.