Stress has been considered an important pleiotropic risk factor for developing psychopathology. However, vulnerability to stress is highly variable among individuals. This difference can be linked to the functional variability of one of the major axes regulating stress response; the HPA axis. Indeed, the HPA axis functionality can be influenced by environmental factors and can affect neurodevelopment in crucial periods. Moreover, variability in reactivity to stress is also partially genetically determined. Such evidence implies that a dysregulation of the HPA axis can constitute an endophenotype that, through genetic-environment interaction, will contribute to vulnerability to psychopathology. 22q11.2 Deletion Syndrome (22q11.2DS) is a neurodevelopmental disorder associated with a high genetic risk of developing multiple psychiatric disorders. Due to the genetic homogeneity of the population and its elevated risk of developing psychopathologies, 22q11.2 DS population could represent a unique model to study the effects of HPA axis dysregulation on psychiatric disorders and brain maturation.