The hippocampal formation is involved in a wide range of disorders, including Alzheimer's disease, schizophrenia, and depression. Recent neuroimaging studies show that these disorders differentially affect distinct subregions of the hippocampal circuit. Some disorders are associated with hypometabolism, while others show hypermetabolism. These observations suggest a unified pathophysiological framework for hippocampal dysfunction. The hippocampal formation is a complex circuit with functionally and molecularly distinct subregions. Neuroimaging and neuropsychological studies have implicated the hippocampal formation in various disorders, but these disorders have distinct pathogenic mechanisms. High-resolution imaging techniques can visualize and assess individual hippocampal subregions, helping to identify differentially affected areas. The concept of regional vulnerability is well established, with some subregions being more vulnerable to certain disorders. For example, CA1 is vulnerable to vascular disease, while the dentate gyrus is vulnerable to adrenalectomy. Functional imaging techniques have identified that some hippocampal-based disorders may cause 'gain of function' symptoms by stimulating hippocampal outflow areas. The pathophysiological framework of hippocampal dysfunction is based on regional vulnerability and metabolic state. The hippocampal formation spans the temporal lobes and is organized into multiple subregions. The entorhinal cortex serves as the gateway into the hippocampal formation and receives input from various regions. The subiculum and CA1 are the main outflow areas of the hippocampal circuit. The hippocampal long axis is functionally organized, with posterior parts involved in memory and cognitive processing, and anterior parts involved in other complex behaviors. The entorhinal cortex is differentially affected in Alzheimer's disease, while CA1 is differentially affected in vascular disease. The hippocampal formation is also involved in schizophrenia and depression, with different subregions being affected. The metabolic state of the hippocampal formation can be assessed using imaging techniques, with hypometabolism associated with memory deficits and hypermetabolism associated with psychotic and affective symptoms. The pathophysiological framework helps to understand the mechanisms of these disorders and their phenotypic variability. The framework also helps to identify the subregions that are differentially affected by these disorders. The framework is based on the functional and molecular organization of the hippocampal circuit, and it provides a unified view of hippocampal dysfunction in various disorders.The hippocampal formation is involved in a wide range of disorders, including Alzheimer's disease, schizophrenia, and depression. Recent neuroimaging studies show that these disorders differentially affect distinct subregions of the hippocampal circuit. Some disorders are associated with hypometabolism, while others show hypermetabolism. These observations suggest a unified pathophysiological framework for hippocampal dysfunction. The hippocampal formation is a complex circuit with functionally and molecularly distinct subregions. Neuroimaging and neuropsychological studies have implicated the hippocampal formation in various disorders, but these disorders have distinct pathogenic mechanisms. High-resolution imaging techniques can visualize and assess individual hippocampal subregions, helping to identify differentially affected areas. The concept of regional vulnerability is well established, with some subregions being more vulnerable to certain disorders. For example, CA1 is vulnerable to vascular disease, while the dentate gyrus is vulnerable to adrenalectomy. Functional imaging techniques have identified that some hippocampal-based disorders may cause 'gain of function' symptoms by stimulating hippocampal outflow areas. The pathophysiological framework of hippocampal dysfunction is based on regional vulnerability and metabolic state. The hippocampal formation spans the temporal lobes and is organized into multiple subregions. The entorhinal cortex serves as the gateway into the hippocampal formation and receives input from various regions. The subiculum and CA1 are the main outflow areas of the hippocampal circuit. The hippocampal long axis is functionally organized, with posterior parts involved in memory and cognitive processing, and anterior parts involved in other complex behaviors. The entorhinal cortex is differentially affected in Alzheimer's disease, while CA1 is differentially affected in vascular disease. The hippocampal formation is also involved in schizophrenia and depression, with different subregions being affected. The metabolic state of the hippocampal formation can be assessed using imaging techniques, with hypometabolism associated with memory deficits and hypermetabolism associated with psychotic and affective symptoms. The pathophysiological framework helps to understand the mechanisms of these disorders and their phenotypic variability. The framework also helps to identify the subregions that are differentially affected by these disorders. The framework is based on the functional and molecular organization of the hippocampal circuit, and it provides a unified view of hippocampal dysfunction in various disorders.