Methotrexate (MTX) is the cornerstone to management across a variety of rheumatic diseases. Effective use and adherence to MTX treatment is dependent on toxicity prevention and management. The major deterrents to patient tolerability and adherence can include GI upset, hepatic transaminase elevation, stomatitis, hair loss, and CNS toxicity. Many rheumatologists are familiar with employing supplementation of folic acid and folinic acid, as well as a change from oral to subcutaneous (SC) MTX, to help combat MTX toxicity. There are, however, more potential strategies in a rheumatologist's armamentarium to ameliorate side effects and improve adherence, including vitamin A supplementation and dextromethorphan. Herein, we will provide a review of the literature (both rheumatologic and oncologic) and expert opinion in terms of managing methotrexate toxicity and improving adherence in rheumatic diseases.