Post-transplant diabetes mellitus (PTDM) is a key risk factor for cardiovascular disease, which itself is a leading cause of death with a functioning graft. In a published review of the literature on PTDM and immunosuppression, most cases of PTDM were diagnosed within the first 3 months post-transplantation. In renal transplantation, the type of immunosuppressive regimen accounted for 74% of the variability recorded in the 12 month cumulative incidence of PTDM between studies (P = 0.0004), with inclusion of corticosteroids and/or high-dose ciclosporin or tacrolimus being the main risk factors for development of PTDM. Other key risk factors were recipient age and non-white ethnicity. The diabetic potential of any immunosuppressive protocol depends on the combination of agents used and the corresponding doses. Therefore, we conducted an analysis to investigate the impact of different tacrolimus-based regimens employed over the past decade together with the time of study initiation on the incidence of PTDM. There was a progressive decline in the incidence of PTDM with year of study initiation, from 20% in the early 1990s to 0-5% most recently. The low incidences of PTDM were achieved with those protocols employing lower blood levels of tacrolimus and/or corticosteroid elimination. These results emphasize the importance of reducing the immunosuppressive medication load and the role of corticosteroids in the development of PTDM. Evolving tacrolimus-based immunosuppressive protocols for renal transplantation over the last 10 years, particularly in terms of tacrolimus dosing and corticosteroid elimination, has led to a reduction in PTDM-related morbidity without compromising efficacy.