The cytoskeleton is a phylogenetically well-preserved structure that plays a key role in cell physiology. Dynamic and differential changes in cytoskeletal organization occur in cellular processes according to the cell type and the specific function. In neurons, microtubules, microfilaments and intermediate filament (IF) rearrangements occur during axogenesis, and neurite formation which eventually differentiate into axons and dendrites to constitute synaptic patterns of connectivity. In epithelial cells, dynamic modifications occur in the three main cytoskeletal components and phosphorylation of cytoskeletal associated proteins takes place during the formation of the epithelial cell monolayer that eventually will transport water. In pathological processes such as neurodegenerative and psychiatric diseases an abnormal cytoskeletal organization occurs. Melatonin, the main product secreted by pineal gland during dark phase of the photoperiod, is capable of influencing microfilament, microtubule and IF organization by acting as a cytoskeletal modulator. In this paper we will summarize the evidence which provides the data that melatonin regulates cytoskeletal organization and we describe recent findings, which indicate that melatonin effects on microfilament rearrangements in stress fibers are involved in the mechanism by which the indole synchronizes water transport in kidney-derived epithelial cells. In addition, we review recent data, which indicates that melatonin protects the neuro-cytoskeletal organization from damage caused by free radicals contributing to cell survival, in addition to the already described mechanism elicited by the indole to prevent apoptosis and to scavenge free radicals. Moreover, we discuss the implications of an altered cytoskeletal organization for neurodegenerative and psychiatric illnesses and its re-establishment by melatonin.