Executive function allows us to interact with the world in a purposive, goal-directed manner. It relies on several cognitive control operations that are mediated by different regions of the prefrontal cortex. While much of our knowledge about the functional subdivisions of the prefrontal cortex comes from the systematic assessment of patients with brain damage, animal models have served as the predominant tool for investigating specific structure-function relationships within the prefrontal cortex, especially as they relate to complex executive behaviors. These studies generally involve the targeted disruption of neural circuits combined with behavioral testing using carefully designed cognitive paradigms. In this review, I will describe a broad range of such experiments conducted in rats and monkeys that together reveal the distinct contributions of dorsal, medial, and ventral prefrontal cortex to different aspects of executive function. The effects of lesions and local pharmacological manipulations have provided valuable insights into the neural underpinnings of executive function and its neurochemical modulation. Despite the challenges associated with establishing a precise homology between animal models of prefrontal function and the human brain, such models currently offer the best means to systematically investigate the cognitive building blocks of executive function. This helps define the neural circuits that lead to a range of neurological and psychiatric disorders and facilitate the development of effective therapeutic strategies to ameliorate the associated cognitive impairments.