Atopic dermatitis (AD) is a chronic itching (pruritic) skin disease. It results from a complex interplay between strong genetic and environmental factors. Genome screens of families with AD have implicated chromosomal regions that overlap with other skin diseases and with inflammatory and autoimmune diseases. These, together with candidate gene studies, provide novel insights into the pathogenesis of AD. The findings suggest a common theme of generalized epidermal dysfunction manifesting as a compromised skin barrier and failure to protect against, or aberrant responses to, microbial insults and antigens. Recent genetic advances with high-throughput methods for gene identification, such as DNA microarrays and whole-genome genotyping, will help further dissect this complex trait. This will aid disease-defining criteria and focused therapies for AD.