Tacrolimus is a calcineurin inhibitor used as an integral part of an immunosuppressive regimen after kidney transplantation. It was first approved in 1997 for prevention of acute rejection in kidney transplantation, and in the last decade it has become the calcineurin inhibitor of choice. Clinical trials have shown tacrolimus to be superior to cyclosporine, another calcineurin inhibitor, in terms of acute rejection prevention and allograft survival. Although switching from cyclosporine to tacrolimus has improved outcomes of kidney transplantation and eliminated cyclosporine's adverse effects, tacrolimus itself has many undesirable effects such as nephrotoxicity, neurotoxicity, post-transplant diabetes mellitus, and electrolyte disorders. Another concerning adverse effect of tacrolimus is BK polyomavirus associated nephropathy which occurs more frequently in those patients who use tacrolimus than those who use cyclosporine. To alleviate these concerning adverse effects, several strategies have been adopted that aim at minimizing exposure to tacrolimus, while keeping its positive effect on acute rejection. One of these strategies includes combining tacrolimus with other immunosuppressive agents, such as mycophenolate mofetil, azathioprine, or corticosteroids. Nonadherence is a common and major cause of kidney transplantation failure. To improve adherence to therapy, new formulations of the drug have been developed. Once-daily prolonged release formulations (Advagraf) of tacrolimus may improve adherence and long-term outcomes compared to twice-daily immediate release formulations. A new extended-release formulation (Envarsus) has been developed and it has been shown to be equally effective in acute rejection prevention, but it remains to be seen if it has fewer adverse effects than Advagraf. It also remains to be seen if a new and better drug will be developed that will replace tacrolimus’ role, or if maybe a new combination of some familiar drugs will be shown as a better solution.