Although there are few endemic species, a wide variety of species are found in the region, including large predators such as the lion (Panthera leo), cheetah (Acinonyx jubatus), leopard (Panthera pardus), spotted hyena (Crocuta crocuta), brown hyena (Parahyaena brunnea), and African wild dog (Lycaon pictus pictus). Birds of prey include the secretarybird (Sagittarius serpentarius), martial eagle (Polemaetus bellicosus) and other eagles, the giant eagle owl (Bubo lacteus) and other owls, falcons, goshawks, kestrels, and kites. Other animals include wildebeest, springbok, gemsbok and other antelopes, Cape porcupines (Hystrix africaeaustralis), and ostriches.

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The San people have lived in the Kalahari for 20,000 years as hunter-gatherers. They hunt wild game with bows and poisoned arrows and gather edible plants, such as berries, melons and nuts, as well as insects. The San get most of their water requirements from plant roots and desert melons found on or under the desert floor. They often store water in the blown-out shells of ostrich eggs. The San live in huts built from local materials—the frame is made of branches, and the roof is thatched with long grass. Most of their hunting and gathering techniques replicate pre-historic tribes. Bantu-speaking Tswana, Kgalagadi, and Herero and a small number of European settlers also live in the Kalahari desert.