In 2020, the American Academy of Dermatology (AAD) and the National Psoriasis Foundation (NPF) released a set of guidelines for the management of psoriasis in adults with systemic nonbiologic therapies, including acitretin, apremilast, cyclosporine, fumaric acid esters, methotrexate, and tofacitinib. This review addresses dosing, efficacy, toxicity, drug-related interactions, and contraindications alongside evidence-based treatment recommendations for each systemic therapy. Important considerations for treatment such as drug selection, initiation of therapy, drug monitoring, and patient management also are discussed. Physicians are encouraged to use these recommendations to guide treatments based on individual patient needs and disease characteristics.