The hippocampus, a critical brain region for learning and memory, is vulnerable to various insults, including neuroactive pathogens, neurotoxins, neurological conditions, trauma, aging, and neurodegenerative diseases. This review explores the vulnerability of the hippocampus to these insults and links it to blood-brain barrier (BBB) dysfunction. The BBB, composed of endothelial cells and supporting cells, protects the brain's internal environment. However, the hippocampal BBB is more fragile and susceptible to disruption compared to other brain areas, potentially contributing to hippocampal damage. Neuroactive pathogens like rabies and herpes simplex virus (HSV) affect the hippocampus, though rabies does not damage it first, while HSV does. Neurotoxins such as alcohol, arsenic, organochloride and organophosphate pesticides, and lead also damage the hippocampus, with arsenic showing the strongest evidence of initial damage. Neurological conditions like epilepsy and migraine are associated with hippocampal damage, with epilepsy showing BBB disruption. Trauma, particularly early-life stress, is linked to hippocampal damage and BBB changes. Aging leads to hippocampal and BBB deterioration, with age-related changes in the hippocampus being more pronounced. Neurodegenerative diseases like Alzheimer's disease are closely linked to hippocampal damage, with the hippocampus being a key target. The review highlights that the hippocampus is more vulnerable to insults compared to other brain areas, and that BBB dysfunction may play a significant role in the harmful effects of these insults on memory and cognition. Protecting the hippocampal BBB could help prevent or alleviate the damage caused by various insults.The hippocampus, a critical brain region for learning and memory, is vulnerable to various insults, including neuroactive pathogens, neurotoxins, neurological conditions, trauma, aging, and neurodegenerative diseases. This review explores the vulnerability of the hippocampus to these insults and links it to blood-brain barrier (BBB) dysfunction. The BBB, composed of endothelial cells and supporting cells, protects the brain's internal environment. However, the hippocampal BBB is more fragile and susceptible to disruption compared to other brain areas, potentially contributing to hippocampal damage. Neuroactive pathogens like rabies and herpes simplex virus (HSV) affect the hippocampus, though rabies does not damage it first, while HSV does. Neurotoxins such as alcohol, arsenic, organochloride and organophosphate pesticides, and lead also damage the hippocampus, with arsenic showing the strongest evidence of initial damage. Neurological conditions like epilepsy and migraine are associated with hippocampal damage, with epilepsy showing BBB disruption. Trauma, particularly early-life stress, is linked to hippocampal damage and BBB changes. Aging leads to hippocampal and BBB deterioration, with age-related changes in the hippocampus being more pronounced. Neurodegenerative diseases like Alzheimer's disease are closely linked to hippocampal damage, with the hippocampus being a key target. The review highlights that the hippocampus is more vulnerable to insults compared to other brain areas, and that BBB dysfunction may play a significant role in the harmful effects of these insults on memory and cognition. Protecting the hippocampal BBB could help prevent or alleviate the damage caused by various insults.