The intensivist caring for the critically ill transplant patient must be knowledgeable in the management of immunosuppression or have expert help. Critical illness often has a major impact on the absorption and metabolism of immunosuppressive drugs, increasing or decreasing net immunosuppression. Too little immunosuppression brings the risk of graft loss, while too much increases the morbidity and mortality of serious infection. Optimum management often requires the skillful manipulation of dosage and/or routes of drug delivery. In many cases of life-threatening infection, immunosuppression must be discontinued altogether and restarted prior to significant graft injury. The cost of miscalculation is very high. Loss of a renal, pancreas, or small bowel transplant is tragic, while loss of a heart, lung, or liver is usually fatal. Unfortunately the management of immunosuppression is becoming more complex. As the field of transplantation matures, new immunosuppressants are being introduced. Also, more experience and growing numbers of clinical trials are making the required knowledge base ever larger. Each type of transplant has its own set of evolving immunosuppression strategies. This review presents the basic mechanisms of the most widely used drugs and the dangers of immunosuppression. The drugs are then discussed in the context of liver, small bowel, kidney, pancreas, heart, and lung transplantation. Finally, a brief section on the practical pharmacokinetics of the drugs is presented.