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The African naked mole rat (Heterocephalus glaber) is a small, eusocial rodent that lives in large colonies consisting of up to 295 individuals. Their skin is pink and translucent, and naked mole rats have a distinct set of incisors that protrude externally from the mouth so that they can close their lips behind their teeth while using the teeth to dig tunnels, toilets, and nest chambers. They construct and inhabit complex underground tunnel systems in the Horn of Africa where they are protected from climate extremes and predators on the surface, but still face limited resources (sparsely distributed food), and a biologically challenging environment where there is a depletion of oxygen and an accumulation of carbon dioxide from many respirating individuals living in an unventilated space. This is particularly an issue in the communal nest chambers where animals gather to huddle and sleep. Data from Zions et al. show that the nest chambers in colonies of captive naked mole rats have significantly, and substantially higher concentrations of CO2 compared to other compartments in the housing system. They also showed that on average, colony members spent more than 70% of their time in the nest chamber, exposed to elevated CO2. Naked mole rats have a multitude of biological adaptations that make them specialized for life in humid, congested, poorly ventilated burrows. Subsequently, this species is a fascinating and important nontraditional model for biomedical research. Studies have focused on topics such as tolerance to hypoxia and hypercapnia, extreme longevity, resistance to cancer, and insensitivity to chemical pain. One remarkable feature that naked mole rats display is the lack of Substance P from their peripheral nerves. Substance P is associated with pain from a variety of irritants such as carbon dioxide (CO2), acid, capsaicin, and ammonia, as well as itch-like pruritogen, like histamines. Lack of Substance P is presumably an adaptation to reduce the negative effects of living in a high CO2 atmosphere, which would cause a burning sensation in the nasal cavity and around the eyes, as well as acidosis in the lungs that causes pulmonary edema. This chapter reviews how this feature affects their physiology and behavior. For example, naked mole rats show a blunted response to inflammatory pain, complete insensitivity to irritants such as capsaicin, ammonia, and acid, and they do not show a scratching response to histamine.