Tissue-selective recruitment of lymphocytes to peripheral organs, such as the skin, is crucial for spatial compartmentalisation within the immune system as well as immune surveillance under normal conditions. In addition, this process plays a key role for the pathogenesis of various diseases including common inflammatory disorders such as atopic dermatitis or psoriasis, but also malignancies such as cutaneous T cell lymphomas. Recruitment of lymphocytes to the skin is a highly complex process that involves adhesion to the endothelial lining, extravasation, migration through the connective tissue, and, finally, localisation of a subpopulation of lymphocytes to the epithelial compartment, the epidermis. An intertwined network of constitutively expressed and inducible cytokines, chemokines and other mediators provides guidance for lymphocyte migration, and a large number of adhesion receptors mediate sequential steps of cell–cell- and cell–substrate-interactions resulting in tissue-specific localisation of immune cells. Selectively targeting the functions of one or several key molecules involved in this complex cascade promises exciting new therapeutic options for treating inflammatory disorders, but at the same time, bears considerable imponderables which will be discussed in this article.