Systemic autoimmune diseases may be progressive and lead to organ system dysfunction and premature death. Current treatment paradigms are usually predominantly based on the administration of immunosuppressive and/or immunomodulatory drug therapy. Such therapy can stabilize systemic manifestations of connective tissue disease (CTD) and may put the disease into remission, and many of these agents are commonly used to treat CTD-associated interstitial lung disease (ILD). Although these agents have largely revolutionized the treatment of the systemic autoimmune diseases, adverse reactions, which can be serious and life threatening, to the various immunosuppressive agents used in the treatment of CTD can occur. Treating physicians must be aware of mechanisms of action of various immunosuppressive agents and be able to recognize the potential adverse reactions that may occur with therapy as well as potentially harmful effects on fetal development. Appropriate monitoring may prevent or limit toxicity from these agents, and knowledge of drug-drug interactions is essential when these agents are prescribed.