Allergic reactions are not confined to the area they originated, but assume a secondary systemic, nonanaphylactic element. This element has two consequences: it feeds back into the site of the original reaction and it leads to the development of distant local manifestations. The well-established interactions between the nasal and the lower airways in allergic disease could be viewed as an example of this model. Interactions between the nasal mucosa and the paranasal sinuses, as well as interactions between the respiratory system, the skin, and the gastrointestinal tract have been described and may also fall under the same category. Two conduits of the systemic element of allergic disease are proposed: the systemic circulation and the nervous system. The mechanisms that lead to the development of the systemic element, and particularly the mechanisms of distant manifestations after a local allergic reaction have not been elucidated, but they probably include intricate interactions between the classic mediators of the acute allergic reaction, locally- and systemically-produced cytokines and neurotrophins, the vascular epithelium and the adhesion molecule system, the chemokine network, antigen-presenting dendritic cells and their interactions with T-lymphocytes, as well as a strong bone marrow component. From this perspective, the systemic element presents an exciting area of current and future research in allergic disease.