The prefrontal cortex (PFC), a cortical region that was once thought to be functionally insignificant, is now known to play an essential role in the organization and control of goal-directed thought and behavior. Neuroimaging, neurophysiological, and modeling techniques have led to tremendous advances in our understanding of PFC functions over the last few decades. It should be noted, however, that neurological, neuropathological, and neuropsychological studies have contributed some of the most essential, historical, and often prescient conclusions regarding the functions of this region. Importantly, examination of patients with brain damage allows one to draw conclusions about whether a brain area is necessary for a particular function. Here, we provide a broad overview of PFC functions based on behavioral and neural changes resulting from damage to PFC in both human patients and nonhuman primates. Szczepanski and Knight provide a broad overview of what is currently known about the functions of different prefrontal cortex (PFC) regions based on neurological, neuropsychological, and neuropathological studies of human patients and nonhuman primates with focal brain damage to PFC.