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The recent discovery of Denisovans (1, 2) and genetic evidence of their hybridization with modern human populations now found in Island Southeast Asia, Australia, and the Pacific (3) are intriguing and unexpected. The reference specimen for the Denisovan genome (4), a distal phalanx from a young girl, was recovered from the geographically distant Denisova Cave in the Russian Altai mountains. Three Denisovan mitochondrial genomes have been generated from material in the cave, dated by poorly associated fauna (5) at more than 50,000 years old. The diversity of these genomes indicates that the Denisovan population had a larger long-term average size than that of the Neandertals (6, 7), suggesting that the Denisovans were formerly widespread across mainland East Asia. However, interbreeding with modern humans only appears to have occurred in remote Island Southeast Asia, requiring marine crossings and raising questions about the distribution and fossil record of Denisovans in Island Southeast Asia.