Atopic dermatitis is a common, chronic, relapsing skin disorder characterized by eczematous lesions and intense pruritus, associated with reduced quality of life. Advanced systemic therapies (injectable biologics and oral Janus kinase inhibitors [JAKis]) for moderate-to-severe atopic dermatitis have transformed the options for patients. Dupilumab, a biologic targeting the interleukin-4 receptor, is now approved for patients as young as 6 months and improves comorbid allergic conditions, such as asthma and eosinophilic esophagitis. In the past 4 years, tralokinumab and lebrikizumab (both targeting interleukin-13) and the interleukin-31 receptor inhibitor, nemolizumab, have been approved for adolescents and adults. In contrast, oral JAKis, such as upadacitinib, abrocitinib, and baricitinib, inhibit the downstream JAK-signal transducers and activators of transcription pathway, providing rapid relief of pruritus and inflammation. Approved for adolescents and adults in the United States, JAKis expand therapeutic flexibility but carry greater safety considerations. This review highlights key systemic agents and discusses practical considerations in therapy selection.