Mesenchymal stem cells (MSCs) are multipotent cells that have the capability of differentiating into adipogenic, osteogenic, chondrogenic, and neural cells. With these multiple capabilities, MSCs have been highly regarded as effective transplantable cell source for regenerative medicine. A large bank of these cells can be found in several regions of the human umbilical cord (hUC) including the umbilical cord lining, the subendothelial layer, the perivascular zone, and most importantly in Wharton’s jelly (WJ). These cells, all umbilical cord-derived MSCs, are very durable, have large loading capacities, and are considered ethical to harvest because the umbilical cord is often considered a waste. These logistical advantages make WJ as appealing source of stem cells for transplant therapy. In particular, WJ is a predominantly good source of cells because MSCs in WJ (WJ-MSC) are maintained in a very early embryological phase and therefore have retained some of the primitive stemness properties. WJ-MSCs can easily differentiate into a plethora of cell types leading to a variety of applications. In addition, WJ-MSCs are slightly easier to harvest compared to other MSCs (such as bone marrow-derived MSCs). The fascinating stemness properties and therapeutic potential of WJ-MSCs provide great promise in many aspects of regenerative medicine and should be considered for further investigations as safe and effective donor cells for transplantation therapy in many debilitating disorders, which are discussed here. We previously reviewed WJ-MSCs therapeutic potential [1] and now provide an update on their recent preclinical and clinical applications.