Atopic dermatitis (AD) is one of the most common inflammatory skin diseases affecting children and adults. The intense pruritus and rash can be debilitating, significantly impairing quality of life. Until recently, treatment was largely nonspecific and, in severe disease, sometimes ineffective and/or fraught with many side effects. Now, multiple agents targeting specific disease pathways are available or in development. Two new therapies, crisaborole and dupilumab, have become available since 2016, and dupilumab has dramatically improved outcomes for adults with severe AD. This article provides an overview of AD, including strategies for differential diagnosis and assessment of disease severity to guide treatment selection. Key clinical trials for crisaborole and dupilumab are reviewed, and other targeted treatments now in development are summarized. Two cases, representing childhood-onset and adult-onset AD, are discussed to provide clinical context for diagnosis, severity assessment, and treatment selection and outcomes.