Abstract: Endoplasmic reticulum (ER) is an intracellular organelle that contributes to efficacious protein synthesis, folding, assembly and transportation. When the normal functions of the ER are perturbed, ER stress is generated which in turn activates an unfolded protein response (UPR). UPR helps in combating this ER stress only at its threshold level, via the inhibition of protein synthesis. This is essentially mediated through increased chaperones and decreased proteins synthesis. Although when the cell undergoes continued ER-stress, UPR ultimately converges to cell-apoptosis, which leads to loss of MSCs viability. Therefore, a delineation into the molecular mechanisms of UPR would be an insightful attempt to curb the prominent loss of MSCs post-transplant. The regenerative potential of MSCs, along with their ubiquitous source of origin, offers vast opportunities with respect to the applications in diverse interdisciplinary sectors of research. But the prevalent loss of MSCs due to certain factors like reactive oxygen species (ROS), hypoxia-reperfusion (H/R), anoikis and inflammation, results in lack of persistence of transplanted MSCs. These hostile conditions contribute to an up surged endoplasmic reticulum stress. Hence, the current review aims at elucidating the mechanisms of the unfolded protein response and its regulation for improving MSCs viability. Lay Summary: A major roadblock for successful use of adult stem cells in practice is their poor survivability once introduced in the patient’s body. The stem cells tend to die quickly due to stress caused by activation of the unfolded protein response (UPR) pathway. Hence if we can target this UPR pathway (de-activation), then the cells might be able to survive for longer period of time that can help in regeneration of the desired tissue in our body. Future Works: Future work can focus on designing therapies that can specifically inhibit UPR activation in stem cells pre and post transplantation such that they are able to survive and help in the desired tissue regeneration inside our body. © 2019, The Regenerative Engineering Society.