While pancreas transplantation has evolved within two decades from a frustrating and poorly-accepted therapeutic option to a highly successful procedure, the respective benefits of the successive surgical and immunosuppressive developments have remained unclear. The aim of this study was to determine using an evidence-based methodology, which novel approaches have contributed to the current results and whether pancreas transplantation is cost-effective. Out of 2481 articles, 102 analyzed either surgical or immunosuppressive aspects of pancreas transplantation. Urological complications were more frequent in bladder over enteric drainage (range: 62-63% vs. 12-20%, p = 0.0001), but without significant difference in patient or graft survival. Portal drainage was associated with a trend toward fewer complications and better hyperinsulinemia control over systemic drainage in retrospective studies. Immunosuppression combining induction therapy, a calcineurin inhibitor, mycophenolate mophetil (MMF) and corticosteroids were associated with a 40% decreased incidence of rejection (p = 0.01) and an increase in graft survival above 90% at 1 year (p < 0.05). Pancreas transplantation is highly cost-effective compared to conservative alternatives. We conclude that despite a paucity of large studies, enteric drainage should be recommended but the benefits of portal venous drainage remain debated. Quadruple immunosuppression protocols including induction therapy should be the standard regimen.