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During evolution, the prefrontal region grew in size relative to the rest of the cortex. It reached its largest extent in the human brain, where it constitutes 30% of the total cortical area. This growth was accompanied by phylogenetic differentiation of the cortical areas. It has been argued that the human brain holds prefrontal regions that are both qualitatively and functionally unique. Present-day neuroscientists studying the prefrontal cortex increasingly use mice. An important goal is to reveal how the prefrontal cortex enables complex behavior. However, the prefrontal cortex still lacks a conclusive definition. The structure and function of this brain area across species remain unresolved. This state of affairs is often overlooked, warranting renewed focus on what the prefrontal cortex is and does.