Atopic dermatitis (AD) is a recurrent, chronic, inflammatory, itchy skin disorder that affects up to 20% of the pediatric population and 10% of the adult population worldwide. Onset typically occurs early in life, and although cardinal disease features are similar across all ages, different age groups and ethnicities present distinct clinical characteristics. The disease imposes a significant burden in all health-related quality of life domains, both in children and adults, and a substantial economic cost both at individual and national levels. The pathophysiology of AD includes a complex and multifaceted interplay between the impaired dysfunctional epidermal barrier, genetic predisposition, and environmental contributors, such as chemical and/or biological pollutants and allergens, in the context of dysregulated T{}_{\text{H}}2 and T{}_{\text{H}}17 skewed immune response. Regarding the genetic component, the loss of function mutations encoding structural proteins such as filaggrin, a fundamental epidermal protein, and the more recently identified variations in the epidermal differentiation complex are well-established determinants resulting in an impaired skin barrier in AD. More recently, epigenetic factors have facilitated AD development, including the dysbiotic skin microbiome and the effect of the external exposome, combined with dietary disorders. Notably, the interleukin (IL)-31 network, comprising several cell types, including macrophages, basophils, and the generated cytokines involved in the pathogenesis of itch in AD, has recently been explored. Unraveling the specific AD endotypes, highlighting the implicated molecular pathogenetic mechanisms of clinically relevant AD phenotypes, has emerged as a crucial step toward targeted therapies for personalized treatment in AD patients. This review aims to present state-of-the-art knowledge regarding the multifactorial and interactive pathophysiological mechanisms in AD.