Recent animal and clinical studies report promising results for the therapeutic utilization of stem cells in regenerative medicine. Mesenchymal stem cells (MSCs), with their pluripotent nature, have advantages over embryonic stem cells in terms of their availability and feasibility. However, their proliferative activity is destined to slow by replicative senescence, and the limited proliferative potential of MSCs not only hinders the preparation of sufficient cells for in vivo application, but also draws a limitation on their potential for differentiation. This calls for the development of safe and efficient means to increase the proliferative as well as differentiation potential of MSCs. Recent advances have led to a better understanding of the underlying mechanisms and significance of cellular senescence, facilitating ways to manipulate the replicative lifespan of a variety of primary cells, including MSCs. This paper introduces a class of proteins that function as senescence suppressors. Like tumor suppressors, these proteins are lost in senescence, while their forced expression delays the onset of senescence. Moreover, treatments that increase the expression or the activity of senescence suppressors, therefore, cause expansion of the replicative and differentiation potential of MSCs. The nature of the activities and putative underlying mechanisms of the senescence suppressors will be discussed to facilitate their evaluation.