Despite the intense interest in biological agents, traditional immunosuppressive drugs remain the mainstays of treatment for systemic rheumatic diseases that involve the lung. Herewith, we review the mechanism of action, administration and clinical use of immunosuppressive drugs, including cyclophosphamide, chlorambucil, azathioprine, methotrexate, leflunomide, cyclosporine, and mycophenolate mofetil. Emphasis is placed on the use of sequential therapies, in which cyclophosphamide is used to induce a remission, and then drugs such as methotrexate or azathioprine are used to maintain the remission. In addition, new regimens that avoid the use of cyclophosphamide for severe forms of vasculitis such as Wegener's granulomatosis have been recently described. Finally, significant benefit has been found when interstitial lung disease due to scleroderma is treated with cyclophosphamide. This represents the first evidence that immunosuppressive drugs are efficacious in rheumatic disease-associated interstitial fibrosis and provides a rationale for developing therapeutic regimens that optimize efficacy and safety.