Immunomodulation is essential for controlling the immune system to maintain efficient immune surveillance and inflammation. Both arms of immunomodulation, namely immunostimulation and immunosuppression, are equally crucial in setting the optimal balance of immune response. However, diseases or conditions such as autoimmune diseases, tissue rejection due to transplantation and chronic inflammation require downregulation of overwhelming immune reactions. The conventional immunosuppressive drugs prevent the activation of immune cells, yet create an unsafe condition with toxic adverse effects. In such predicament, mesenchymal stem cells (MSCs) emerged as one of the safe immunosuppressive regiments and widely tested in clinical trials for numerous chronic inflammatory dis-eases. Mesenchymal stem cells are the origin of the stromal/mesenchymal cells in almost all solid organs, including the pulp of the tooth. In addition to providing structural support to the organ, MSCs participate in the tissue repair and regeneration by ameliorating an overly activated immune response locally and systemically. Regardless of the source, MSCs profoundly suppress the proliferation and effector functions of both innate and adaptive immune cells. The mechanism of inhibition primarily took place in the early phase of cell cycle and mediated via suppression of mainstream signalling pathways that involve cyclins and other cell cycle proteins. The antiproliferative activity of MSCs is not only limited to the healthy immune cells but extends to the various tumour cells of the immune system. Similarly, an array of cell signalling pathways that executed by cell cycle proteins found downregulated in the pres-ence of MSCs. The immunosuppressive activity exerted by MSCs is not specific to particular immune cells where it impairs a group of the common cell signalling pathways or putative cell cycle proteins which are vital elements for the proliferation.