Fear and anxiety are adaptive responses but if left unregulated, or inappropriately regulated, they become biologically and socially maladaptive. Dysregulated emotions are manifest in a wide variety of psychiatric and neurological conditions but the external expression gives little indication of the underlying causes, which are inevitably multi-determined. To go beyond the overt phenotype and begin to understand the causal mechanisms leading to conditions characterized by anxiety and disorders of mood, it is necessary to identify the base psychological processes that have become dysregulated, and map them on to their associated neural substrates. So far, attention has been focused primarily on the medial regions of prefrontal cortex (PFC) and in particular their contribution to the expression and extinction of conditioned fear. However, functional neuroimaging studies have shown that the sphere of influence within the PFC is not restricted to its medial regions, but extends into dorsal, ventrolateral (vlPFC) and orbitofrontal (OFC) regions too; although the causal role of these other areas in the regulation of fear and anxiety remains to be determined and in the case of the OFC, existing findings are conflicting. Here, we review the evidence for the contribution of these other regions in negative emotion regulation in rodents and old world and new world monkeys. We consider a variety of different contexts, including conditioned and innate fear, learned and unlearned anxiety and cost-benefit decision-making, and a range of physiological and behavioral measures of emotion. It is proposed that both the OFC and vlPFC contribute to emotion regulation via their involvement, respectively, in the prediction of future outcomes and higher-order attentional control. The fractionation of these neurocognitive and neurobehavioral systems that regulate fear and anxiety opens up new opportunities for diagnostic stratification and personalized treatment strategies.