Irritation and inflammation are complex processes. Several biochemical events are involved in the initiation, amplification and ultimate resolution of an inflammatory sequence, with the exact details depending on the nature of the insult. A wide variety of protocols have been proposed for the estimation of irritation potential, but none is fully accepted as a replacement for the Draize test. This selective review considers ideas generally neglected in toxicological research. Substantial support was found for the hypothesis that neurogenic phenomena play an important role in the irritant response, especially for the difficult case of mild irritation. The hypothesis is open to experimental evaluation by testing capsaicindesensitized animals or those pretreated with recently developed pharmacological antagonists of neuropeptides. Fundamental interactions of perturbants with membranes and plasma proteins that are relevant to the initiation of the neurogenic response to mild irritation are discussed. Technical approaches for alternative assays based on the neurogenic hypothesis are considered.