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Methotrexate (MTX) has been one of the most used anti-inflammatory, antimetabolite, and steroid-sparing drugs in dermatology, it was originally developed as an antineoplastic drug for leukemia which was later introduced as a therapeutic option for psoriasis, rheumatoid arthritis, and, recently, for inflammatory skin diseases. MTX is the drug of choice for the systemic treatment of psoriasis, being an effective, safe, and low-cost option. The use of MTX has extended to other inflammatory diseases such as urticaria, atopic dermatitis, pemphigus vulgaris, bullous pemphigoid, and recently, intralesional therapy for cutaneous tumors. Despite the wide range of potential indications, is still continues to be scarce, and mainly derived from case series and reports and prospective, randomized double-blinded studies are lacking. Herein, we will review the main uses of MTX for skin diseases and the evidence regarding its efficacy and safety.