The oral chemotherapy agent methotrexate remains a mainstay for the treatment of moderate to severe psoriasis after 40 years’ experience. Extensive usage, both for psoriasis and rheumatoid arthritis patients, has continued the reasonable safety profile for this drug when appropriate precautions are taken. The availability of other treatment modalities for severe psoriasis permits a rotational system with periods of time when methotrexate is not used, thereby lessening the risk of long-term side effects. Other chemotherapeutic agents for psoriasis are described, but they are used infrequently.