Recent studies indicate that the majority of clinically important aeroallergens are biochemically active. A diverse range of properties have been demonstrated but most possess either enzymatic activity (principally hydrolytic), enzyme inhibitory activity, low molecular weight ligand transporting or regulatory properties. In addition, some allergens are glycosylated and/or are structurally similar to proteins which have evolved to function in the respiratory system per se. Little attention has been given to the possibility that the biochemical activity of an allergen or any post-translational modifications contribute to sensitization. In this review, mechanisms with the potential to influence immunogenicity are discussed including interaction with respiratory secretions, epithelial disruption, interactions with immunocompetent cells and receptor mediated endocytosis. Given that many aeroallergens are structurally and functionally similar to a variety of endogenous (e.g. lysosomal enzymes) and exogenous proteins (e.g. microbial enzymes and glycoproteins), particular attention has been directed to the latter. This process represents an important non-adaptive defence mechanism which has evolved to recognize and process such proteins and it is feasible that it plays a similar role in the processing of some allergens entering the respiratory system.