OBJECTIVES: To systematically identify and summarise the evidence of renal transplant outcomes, toxicity and adverse effects in order to determine the most effective options. In particular, comparing tacrolimus, the cornerstone of renal transplantation therapy, with newer therapies that have been introduced since 2003. METHODS: An electronic literature search of MEDLINE, Current Contents and the Cochrane Library databases was conducted, plus manual reference checks of all articles involving controlled trials of kidney transplants and immunosuppressive therapy between 2003 and July 2010. Studies were assessed for eligibility and quality by two reviewers who extracted data independently. Studies were classified according to CNI avoidance or reduction, steroid avoidance, and induction therapies. Results were expressed as risk ratio (RR) with 95% confidence intervals (CI). Where necessary, indirect comparison techniques were used to compare different forms of tacrolimus with belatacept. RESULTS: 35 studies from an initial list of 2,895 citations were included in the analysis. Results show CNI avoidance leads to higher incidence of acute rejection (RR 2.52, 95% CI 1.11–5.75), which is a known predictor for graft loss, but reduced chronic allograft nephropathy. Tacrolimus produces better rejection prophylaxis compared with ciclosporin (RR 0.38, 95% CI 0.21­–0.70), and ciclosporin produces lower acute rejection compared with belatacept (RR 0.32, 95% CI 0.19–0.55). Indirect analysis shows that tacrolimus is superior to belatacept in acute rejection prophylaxis (RR 0.18, 95% CI 0.08–0.39), but leads to more cases of a decrease in glomerular filtration rate (GFR) (RR 1.37, 95% CI 0.92–2.03); however, the long-term impact of a reduction in GFR in the context of a CNI-free regimen is not clear at present. CONCLUSIONS: Direct and indirect comparisons demonstrate that CNIs, and in particular tacrolimus, remain superior even against more recent compounds for preventing acute rejection. However, more research needs to be done to find the optimum combination of therapies.