The human brain does not develop in a vacuum according to a set of predetermined blueprints—it is involved in a dynamic interplay with the environment that influences gene expression and ultimately structure and function. Some cortical regions, such as the prefrontal cortex (PFC) undergo structural changes throughout the adolescent period and into early adulthood, making their structure and functions particularly interesting to study with respect to gene-environment interactions. Repeated exposure to stress is a predisposing factor in the emergence of various mental illnesses, such as anxiety and depression, although this is by no means an absolute relationship. While some people appear to be vulnerable to the effects of repeated stressors, others are resilient, and this individual variability is partly due to developmental programming of brain regions involved in modulating stress responding, such as the PFC. In the present book, we will discuss features of adolescent brain development that may provide a basis for neural plasticity in stress responding: the highly protracted development of the PFC, the profound change in interconnectedness among cortical and subcortical brain regions, and the characteristic ‘rise and fall’ pattern for many of the late-developing aspects of neural architecture in PFC and other stress-related brain regions.