Children who are recalcitrant to topical therapy for their moderate to severe plaque psoriasis and/or highly visible lesions may be candidates for systemic therapy. Methotrexate has been the most commonly used systemic agent in children. However, at least 25% of patients are now treated with biologics, especially tumor necrosis factor-α inhibitors, and their use is expanding as their availability, demonstrated safety and efficacy, and practitioner experience are increasing. In the United States, etanercept is Food and Drug Administration approved for ages 6 years and older and ustekinumab for 12 years of age and older. In Europe, adalimumab is also approved for pediatric psoriasis for 4 years of age and older. While biologics have the advantage of less frequent administration, greater and more rapid efficacy than methotrexate, fewer side effects, and a less rigorous need for monitoring, their cost is much higher than that of methotrexate and other systemic medications, concerns about the development of neutralizing antibodies necessitate continuous treatment, and their long-term safety profile remains to be determined.