Organ transplantation is the only effective treatment for patients with end-stage organ failure. Although modern immunosuppressive protocols are very effective and improve quality of life, there is still a need for improvements to eliminate their side effects and to induce transplantation tolerance to allografts. The microRNAs (miRNAs) emerged as promising candidates for regulations of several immune functions. The most advanced research of miRNAs documented that several miRNAs form very complex regulatory networks involved in fine and precise mechanisms of multiple pathophysiological process in cells. This review describes the origin of miRNAs and their action mechanisms by which they regulate several immune and cell biology processes, highlighting the fast progress of miRNA research involved in transplant rejection, recent clinical trials, and describing prospects and possible limitations.