The ability of the early environment to program the hypothalamo–pituitary–adrenal (HPA) axis has been documented in several species. There is considerable evidence that a similar process can also occur in humans. Studies of animals indicate that the phenotype of HPA function following early manipulation depends on the timing and intensity of the manipulation, in addition to the gender of the fetus or neonate. There is considerable interplay between the HPA and the hypothalamo–pituitary–gonadal axes, and emerging evidence indicates that this interaction is modified by early environmental manipulation. Studies are rapidly unraveling the mechanisms that underlie developmental programming of the HPA axis. Understanding these mechanisms could hold the key to the development of therapeutic interventions aimed at reversing the impact of an adverse intrauterine or neonatal environment.