The blood-brain barrier (BBB) is a highly specialized structure that separates the circulating blood from the brain, ensuring protection, homeostasis, and optimal functioning of the central nervous system (CNS). Cerebral endothelial cells, pericytes, astrocytes, and basement membrane form the BBB. The interaction of these elements with neurons and microglia is called the neurovascular unit (NVU). Each component plays a fundamental role in maintaining the integrity and functioning of the BBB. The BBB regulates the transport of molecules between the blood and the brain, and vice-versa, selectively allowing the entry of essential nutrients while preventing the passage of potentially harmful substances, such as toxins and pathogens. This selective permeability is crucial for maintaining an optimal environment for neuronal function and protecting the brain from potential damage. BBB integrity is essential for brain health, and its disruption is a hallmark of many neurological disorders, neurodegenerative diseases, and even aging. BBB disruption has been described in pathologies such as multiple sclerosis, where it facilitates immune cell migration and demyelination. In epilepsy, BBB dysfunction has been considered as contributing factor to the initiation and progression of seizures. In Alzheimer’s disease, BBB’s permeability contributes to neuroinflammation and neuronal damage. Age-related BBB breakdown can lead to toxins, pathogens, or immune cell invasion, which can result in neuronal dysfunction and potentially, neurodegeneration. In this chapter, we will discuss the structure and functions of the BBB, sex-related physiological differences, the impact of conditions like temperature and stress on it, and how its disruption affects brain homeostasis and contributes to disease.