Certainly, achieving and maintaining donor-specific hyporesposiveness is a main challenge nowadays in organ transplantation to improve long-term graft survival. Immunosuppression seems to be mandatory in the majority of renal transplant patients. However, some specific drugs have shown to have interesting immunomodulatory effects, regardless of their immunosuppressive activity. Sirolimus, an immunosuppressive agent with a distinctive action mechanism has shown to be able to directly influence the main two cell subset population in charge of controlling alloimmune responses: regulatory T cells and dendritic cells. Here, we discuss and analyze the main mechanisms by which sirolimus may modulate the alloimmune response, thus facilitating a protolerogenic state in renal transplantation.