A primary aim of neurotoxicology is to identify agents that impact directly on the nervous system with the ultimate goal of identifying any adverse effects associated with exposure. Behavioral, biochemical, electrophysiological and morphological indicators are all suggested as appropriate means for detecting neurotoxicity. A general review of the impact of stress or adrenal axis perturbations on neurotoxicity is provided by the chapter. It illustrates how damage to, chemically-induced alterations in the secretions of, or activation of the adrenal axis may impact on the endpoints used to assess neurotoxicity. Often what are normally considered to be irrelevant variables such as handling, dosing and housing procedure may impact neurotoxicity assessment in both adult and developing organisms. Laboratory animals are not the toxicologist's black box and a better understanding of the changes associated with the procedures utilized in toxicity testing will lead to greater confidence in the data provided by such testing.