Immunosuppressants are prescribed to prevent rejection of transplanted tissues and organs and are also used in the treatment of autoimmune disorders. Consultation-liaison psychiatrists increasingly encounter patients taking these agents as the number of transplant recipients increases and the indications for the use of immunosuppressants expands. These drugs have potentially deleterious physical, mental, and biochemical side effects. In addition, transplant recipients and patients with autoimmune disorders commonly have comorbid illnesses that require pharmacologic treatment. The management of these patients is challenging secondary to the severity of these illnesses, the number of medications prescribed, and the potential for adverse drug-drug interactions. Knowledge of the pharmacokinetic properties of these drugs and the potential for serious drug-drug interactions that cause alterations in serum levels of the immunosuppressant medications is essential. Increased serum levels may cause serious toxic effects and decreased serum levels may lead to rejection of the transplanted organ or worsening of the autoimmune disorder. Adverse events may also occur when serum levels of medications prescribed for comorbid illnesses are altered by administration of immunosuppressants. The pharmacokinetic drug-drug interaction profiles of the glucocorticoids, cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, azathioprine, and monoclonal antibodies are discussed in this review.