Despite a different molecular structure and biochemical properties, cyclosporine and tacrolimus--by inhibiting calcineurin activity--have been shown in the previous two decades of solid organ transplantation to be well tolerated and effective immunosuppressants. Initial randomized clinical trials showed a lower incidence of acute rejection in tacrolimus than in cyclosporine-treated patients, in combination with steroids and azathioprine. But in conjunction with mycophenolate mofetil, the difference in the incidence of acute rejection episodes is less clear. In general, short- and medium-term outcome variables (1-year serum creatinine, graft and patient survival) with cyclosporine and tacrolimus are excellent, and (almost) identical, with both substances having the same intrinsic nephrotoxic potential. On the other hand, cyclosporine and tacrolimus have a different impact on cardiovascular risk factors with tacrolimus having a better profile on arterial tension and lipid metabolism and cyclosporine on glucose metabolism. However, at present no data are available to discern that these differences in risk profile alter patient or graft survival or long-term cardiovascular morbidity/mortality. Therefore, prospective long-term trials are needed to study the quantitative impact of different immunosuppressive agents and concomitant cardiovascular risk factors on long-term patient and graft survival, before evidence-based (patient, graft, or cardiovascular) risk reduction can be firmly claimed by tailoring calcineurin inhibitors.