The array of systemic medications used in the treatment of psoriasis is rapidly expanding. In the United States, methotrexate, retinoids, and cyclosporine are the only systemic drugs approved by the Food and Drug Administration for the treatment of psoriasis. Monitoring and dosage recommendations for these medications are reviewed. Other drugs that are currently available include tacrolimus, mycophenolate mofetil, hydroxyurea, 6-thioguanine, and sulfasalazine. Experience with these drugs is summarized, and dosage and monitoring recommendations in published literature are presented. Combinations of different treatments are addressed and investigational therapies that are in development are reviewed.