Content differentiation models posit that different areas of the prefrontal cortex perform similar operations but differ in terms of the content that is operated on. For example, it has been suggested that the orbitofrontal cortex (OFC) and the dorsolateral prefrontal cortex (DLPFC) perform similar working memory or inhibitory operations, but on different types of content (e.g., reward versus spatial or feature-based versus abstract). In contrast to the above models, process differentiation models posit that different areas of the prefrontal cortex perform fundamentally different operations. Surprisingly, discussions of these dueling models rarely incorporate information about anatomy. The only exception is that advocates of content differentiation models appropriately note that different parts of the prefrontal cortex receive different afferents. Yet, an examination of the anatomy of the OFC and the DLPFC reveal numerous differences in cortical structure and interneuron composition. These structural differences necessitate that the OFC and the DLPFC will have strikingly different computational features. Given such computational differences, strong versions of content differentiation models are untenable. While overarching themes may help explain the operations in both the OFC and the DLPFC, the specific operations performed in the two regions are likely to be both quantitatively and qualitatively different in nature.