Prior to the cyclosporine (CsA) era, there were no long-term survivors from lung transplantation as the immunosuppressive drugs made patients very susceptible to opportunistic infections and anastomotic complications. CsA is a calcineurin inhibitor that binds to cyclophilins and inhibits transcription of interleukin 2 in T cells, thereby preventing proliferation of activated T cells. The initial immunosuppressive regimen at our institution includes CsA, azathioprine, and steroids. Blood levels of CsA (whole blood, TDx assay) are maintained between 250 and 350 ng/mL for 0 to 6 months, 200 to 300 ng/mL for 6 to 12 months, and around 200 ng/mL beyond 12 months following lung transplantation. Nephrotoxicity, hypertension, susceptibility to infections, and malignancy are some of the serious side effects of CsA that limit its therapeutic usefulness. Acute rejection is relatively common with this regimen, and about 60% of all lung transplant recipients are treated for an episode of acute rejection within the first 12 months after lung transplantation. Acute rejection is a probable risk factor for chronic rejection, and obliterative bronchiolitis develops in about 50% of the patients who survive 5 years. Treatment of chronic rejection continues to be a challenge in lung transplantation. CsA and tacrolimus seem to have equivalent results in lung transplantation, although a few patients may benefit from the use of tacrolimus.