Methotrexate is a well-known chemotherapeutic agent, widely used alone or in combination with other drugs in the treatment of cancer. Methotrexate applications in dermatology have significantly expanded over the years. Methotrexate is an established treatment modality for psoriasis; other indications include vitiligo, atopic dermatitis, immunobullous disorders, alopecia areata, neutrophilic dermatoses, and cutaneous T-cell lymphoma. To increase the efficacy and reduce the potential adverse effects, different methotrexate forms and modes of delivery have been investigated including intralesional and topical modalities. Herein, dermatologists are introduced to methotrexate different indications in clinical practice, its mechanism of action, and the in-depth knowledge needed to effectively and safely prescribe methotrexate to their patients with confidence. Mastery of prescribing methotrexate is an essential skill for dermatologists.