Atopic dermatitis (AD) accounts for a significant share of chronic inflammatory skin disorders. There is a niche for the development of biologics to treat recalcitrant autoinflammatory stage AD seen mostly in adults. The heterogeneity of patient response to various existing biotherapies points to involvement of various immune responses and suggests that therapies must preferably target early development of allergen-specific B- and T-cell clones. In addition to immune targets, tissue factors that help restore the normal epidermal environment constitute interesting therapeutic tools. Several approaches are needed to find the appropriate targets in a field where so many have been investigated without definitive proof of concept for human systemic therapy. The keys to success are probably (1) to influence the inflammatory skin pattern towards less pruritogenic effects, requiring us to better understand pruritogenic inflammation and (2) to limit the amplification loop of disease by attacking abnormal regulatory mechanisms which perpetuate skin autoinflammation.