The review discusses the pathophysiological framework of hippocampal dysfunction in aging and various diseases, including Alzheimer's disease, temporal lobe epilepsy (TLE), cognitive aging, post-traumatic stress disorder (PTSD), transient global amnesia, schizophrenia, and depressive and anxiety disorders. The hippocampal formation, a complex circuit spanning the temporal lobes, is implicated in a wide range of disorders, and recent neuroimaging findings suggest that these disorders target distinct subregions of the hippocampal circuit. Some disorders are associated with hypometabolism, while others show hypermetabolism. The review highlights the importance of understanding regional vulnerability and metabolic state in the context of the functional and molecular organization of the hippocampal circuit. The hippocampal formation is organized into functionally and molecularly distinct subregions, including the entorhinal cortex, dentate gyrus, CA1, CA3, and subiculum. High-resolution structural and functional MRI techniques have been used to map the integrity of individual subregions, revealing differential vulnerability patterns in various disorders. For example, vascular disease primarily affects CA1, Alzheimer's disease targets the entorhinal cortex and CA1, and aging differentially targets the dentate gyrus. The review also discusses the metabolic state of the hippocampal formation, noting that hypometabolism is common in Alzheimer's disease, vascular disease, and aging, while hypermetabolism has been observed in schizophrenia and depression. Hypermetabolism in the anterior hippocampus may contribute to gain-of-function symptoms in these disorders, such as psychotic and affective symptoms. The authors propose a pathophysiological framework that integrates regional vulnerability and metabolic state to explain the phenotypic diversity and mechanistic differences among hippocampal disorders. This framework can be used to develop more nuanced neuropsychological tests and to validate theories about the function of individual subregions. The review concludes by discussing the potential of this framework to clarify pathogenic mechanisms and guide therapeutic interventions.The review discusses the pathophysiological framework of hippocampal dysfunction in aging and various diseases, including Alzheimer's disease, temporal lobe epilepsy (TLE), cognitive aging, post-traumatic stress disorder (PTSD), transient global amnesia, schizophrenia, and depressive and anxiety disorders. The hippocampal formation, a complex circuit spanning the temporal lobes, is implicated in a wide range of disorders, and recent neuroimaging findings suggest that these disorders target distinct subregions of the hippocampal circuit. Some disorders are associated with hypometabolism, while others show hypermetabolism. The review highlights the importance of understanding regional vulnerability and metabolic state in the context of the functional and molecular organization of the hippocampal circuit. The hippocampal formation is organized into functionally and molecularly distinct subregions, including the entorhinal cortex, dentate gyrus, CA1, CA3, and subiculum. High-resolution structural and functional MRI techniques have been used to map the integrity of individual subregions, revealing differential vulnerability patterns in various disorders. For example, vascular disease primarily affects CA1, Alzheimer's disease targets the entorhinal cortex and CA1, and aging differentially targets the dentate gyrus. The review also discusses the metabolic state of the hippocampal formation, noting that hypometabolism is common in Alzheimer's disease, vascular disease, and aging, while hypermetabolism has been observed in schizophrenia and depression. Hypermetabolism in the anterior hippocampus may contribute to gain-of-function symptoms in these disorders, such as psychotic and affective symptoms. The authors propose a pathophysiological framework that integrates regional vulnerability and metabolic state to explain the phenotypic diversity and mechanistic differences among hippocampal disorders. This framework can be used to develop more nuanced neuropsychological tests and to validate theories about the function of individual subregions. The review concludes by discussing the potential of this framework to clarify pathogenic mechanisms and guide therapeutic interventions.