Adverse experiences during childhood can have long-lasting impacts on physical and mental health. At the heart of most theories of how these effects are transduced into health impacts is the activity of stress-mediating systems, most notably the hypothalamic-pituitary-adrenocortical (HPA) axis. Here we review the anatomy and physiology of the axis, models of stress and development, the development of the axis prenatally through adolescence, the role of experience and sensitive periods in shaping its regulation, the social regulation of the axis at different points in development, and finally conclude with suggestions for future research. We conclude that it is clear that early adversity sculpts the stress system, but we do not understand which dimensions have the most impact and at what points in early development. It is equally clear that secure attachment relationships buffer the developing stress system; however, the mechanisms of social buffering and how these may change with development are not yet clear. Another critical issue that is not understood is when and for whom adversity will result in hypo- vs hyperactivity of stress-mediating systems. These and other issues are important for advancing our understanding of how early adversity “gets under the skin” and shapes human physical and mental health.