Atopic dermatitis (AD) is a chronic inflammatory condition that significantly affects the quality of life of both patients and their families or caregivers. Recently, treatment for moderate-to-severe AD were limited to conventional immunosuppressive therapies. However, currently, with the approval of biologic treatments and oral small molecules in the past decade, the effective and safe management of patients with AD is possible. Despite these advancements, challenges and unmet needs in clinical practice remain. This includes patients who do not respond well to or cannot tolerate existing treatment options and inadequate therapies that can modify the disease course. This review aimed to provide an overview of the current treatment approach for AD, highlight the current challenges in treatment, and discuss the rationale for novel treatment options and emerging evidence on systemic treatment options for AD.