Methotrexate is a folate antagonist that is a well-established therapy for autoimmune and inflammatory conditions. In some patients, methotrexate is associated with significant side effects and toxicity. Folate supplementation is often used to ameliorate methotrexate-associated side effects and toxicities. We sought to demonstrate that folate supplementation during methotrexate therapy reduces both toxicity and side effects without compromising efficacy. A MEDLINE search of the search terms “methotrexate,” “folic acid,” “folinic acid,” and “leucovorin” was performed and literature relevant to the use of folates as a supplement to methotrexate was reviewed. According to studies reviewed, the use of folate supplements in patients treated with methotrexate reduces the incidence of hepatotoxicity and gastrointestinal intolerance without impairing the efficacy of methotrexate. Both folic acid and folinic acid are equally effective; however, folic acid is more cost effective. It must be noted that there are relatively few studies that have addressed folate supplementation with the use of methotrexate for the treatment of psoriasis. After examining the available data from the literature and drawing from clinical experience, we advise folate supplementation for every patient who receives methotrexate.