Among the numerous functions of melatonin, the control of survival and differentiation of mesenchymal stem cells (MSC) has been recently proposed. These are a heterogeneous population of multipotent elements resident in tissues such as bone and bone marrow, muscle and adipose. MSC are primarily involved in development and regeneration processes, and these properties are now gaining increasing consideration for the development of therapeutic protocols of tissue repair and restoration. Receptor-dependent and -independent responses to melatonin are suggested to occur in these cells. These involve antioxidant or redox-dependent functions of this indolamine as well as secondary effects resulting from autocrine and paracrine responses produced in tissues and through the same MSC. In fact, inflammatory cytokines and adipokines, proangiogenic/mitogenic stimuli, and other mediators that influence the differentiation processes of MSC at different levels, also provide protection that may affect the survival and functional integrity of these cells. Melatonin seems to regulate selected signaling responses that alternatively commit and drive MSC through differentiation into osteogenic, chondrogenic, adipogenic or myogenic lineages. Common pathways appear to function as master regulators of these processes acting at the earliest or irreversible steps of MSC signaling, such as the Wnt/β-catenin/PPARγ pathway, MAPKs, TGF-β signaling and others. In this respect, the effect of melatonin on the adipogenic signaling is worthy of further consideration for regulatory and therapeutic roles in both the physiological and diabetogenic frameworks. These and other aspects of the physiological and pharmacological effects of melatonin as regulators of MSC integrity and differentiation in human tissues are discussed.This article is protected by copyright. All rights reserved.