Objective: Changes in cortical excitability and neuroplasticity are important parts of the neuropathology and pathophysiology of many neuropsychiatric disorders. Noninvasive brain stimulation is a high-potential therapeutic approach to modify cortical activities. One of the most popular of these techniques is transcranial direct current stimulation (tDCS). However, the biological and neurobiological effects of tDCS should be better clarified to enable its optimal use in clinical and therapeutic practices. In this paper, we summarize the neurophysiological and physiological effects and mechanisms of action of tDCS. Method: An update literature review was conducted on the biological responses of tDCS reported in human, in vitro and in vivo studies, with a focus on cellular cascades related to neuroplasticity, neuronal reorganization and inflammation caused by applied direct current electric fields. Results: The regulatory mechanisms of tDCS on motor and cognitive functions can be described by membrane polarization and transmembrane potential with a main subsequent effect on neurotransmission systems, neuronal excitability, synaptic microenvironment and neuronal connectivity to neuronal reorganization and neurogenesis in association with synaptic plasticity as well as inflammatory processes. In general, the effects of tDCS may include acute-or after-effects and direct or indirect effects and can be examined at different levels including the neurochemical, the neuroelectrical and the brain oscillatory levels. Conclusion: A deep understanding of the molecular and cellular responses to tDCS is very important and crucial. This therapeutic technique can be utilized in various clinical trials with a perspective of being routinely suggested and presented to patients with different pathological conditions influencing the central or peripheral nervous system.