The prefrontal cortex (PFC) plays a pivotal role in regulating our emotions. The importance of ventromedial regions in emotion regulation, including the ventral sector of the medial PFC, the medial sector of the orbital cortex and subgenual cingulate cortex, have been recognized for a long time. However, it is increasingly apparent that lateral and dorsal regions of the PFC, as well as neighbouring dorsal anterior cingulate cortex, also play a role. Defining the underlying psychological mechanisms by which these functionally distinct regions modulate emotions and the nature and extent of their interactions is a critical step towards better stratification of the symptoms of mood and anxiety disorders. It is also important to extend our understanding of these prefrontal circuits in development. Specifically, it is important to determine whether they exhibit differential sensitivity to perturbations by known risk factors such as stress and inflammation at distinct developmental epochs. This Special Issue brings together the most recent research in humans and other animals that addresses these important issues, and in doing so, highlights the value of the translational approach.