The hippocampus, a critical brain structure for learning and memory, is vulnerable to a wide range of insults, including neuroactive pathogens, neurotoxins, neurological conditions, trauma, aging, neurodegenerative diseases, and environmental factors. This review assesses the hippocampus's vulnerability to these insults and evaluates whether it is more affected compared to other brain regions. The blood–brain barrier (BBB) dysfunction is also considered as a contributing factor to the harmful effects of these insults. Recent research suggests that the hippocampal BBB is more fragile and prone to disruption compared to other brain areas. The review examines the impact of specific insults, such as rabies, herpes simplex virus (HSV), alcohol, arsenic, insecticides, lead, epilepsy, migraine, early-life stress (ELS), post-traumatic stress disorder (PTSD), aging, and Alzheimer's disease (AD), on the hippocampus and the BBB. The findings indicate that the hippocampus is more vulnerable to insults, and protecting the hippocampal BBB may help prevent or mitigate the harmful effects of many insults on memory and cognition.The hippocampus, a critical brain structure for learning and memory, is vulnerable to a wide range of insults, including neuroactive pathogens, neurotoxins, neurological conditions, trauma, aging, neurodegenerative diseases, and environmental factors. This review assesses the hippocampus's vulnerability to these insults and evaluates whether it is more affected compared to other brain regions. The blood–brain barrier (BBB) dysfunction is also considered as a contributing factor to the harmful effects of these insults. Recent research suggests that the hippocampal BBB is more fragile and prone to disruption compared to other brain areas. The review examines the impact of specific insults, such as rabies, herpes simplex virus (HSV), alcohol, arsenic, insecticides, lead, epilepsy, migraine, early-life stress (ELS), post-traumatic stress disorder (PTSD), aging, and Alzheimer's disease (AD), on the hippocampus and the BBB. The findings indicate that the hippocampus is more vulnerable to insults, and protecting the hippocampal BBB may help prevent or mitigate the harmful effects of many insults on memory and cognition.