Knowledge of the genetic and molecular events underlying the neuroendocrine and behavioural sequelae of the response to stress has advanced rapidly over recent years. The response of an individual to a stressful experience is a polygenic trait, but also involves non-genetic sources of variance. Using a combination of top-down (quantitative trait locus [QTL] and microarray analysis) and bottom-up (gene targeting, transgenesis, antisense technology and random mutagenesis) strategies, we are beginning to dissect the molecular players in the mediation of the stress response. Given the wealth of the data obtained from mouse mutants, this review will primarily focus on the contributions made by transgenesis and knockout studies, but the relative contribution of QTL studies and microarray studies will also be briefly addressed. From these studies it is evident that several neuroendocrine and behavioural alterations induced by stress can be modelled in mouse mutants with alterations in hypothalamic-pituitary-adrenal axis activity or other, extrahypothalamic, neurotransmitter systems known to be involved in the stress response. The relative contribution of these models to understanding the stress response and their limitations will be discussed.