Methotrexate has been used in the treatment of recalcitrant psoriasis for more than 35 years. We examined the significance of impaired spermatogenesis in a young man undergoing methotrexate treatment for severe psoriasis with associated arthritis. A medical geneticist was consulted and a review of the literature was performed. Genetic abnormalities that could lead to mutagenesis include chromosomal abnormalities and single-gene mutations. These aspects are considered and recommendations are made for counseling men undergoing methotrexate therapy so that risks and options can be considered.