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The world's river dolphins (Inia, Pontoporia, Lipotes and Platanista) are among the least known and most endangered of all cetaceans. The four extant genera inhabit geographically disjunct river systems and exhibit highly modified morphologies, leading many cetologists to regard river dolphins as an unnatural group. Numerous arrangements have been proposed for their phylogenetic relationships to one another and to other odontocete cetaceans. These alternative views strongly affect the biogeographical and evolutionary implications raised by the important, although limited, fossil record of river dolphins. We present a hypothesis of river dolphin relationships based on phylogenetic analysis of three mitochondrial genes for 29 cetacean species, concluding that the four genera represent three separate, ancient branches in odontocete evolution. Our molecular phylogeny corresponds well with the first fossil appearances of the primary lineages of modern odontocetes. Integrating relevant events in Tertiary palaeoceanography, we develop a scenario for river dolphin evolution during the globally high sea levels of the Middle Miocene. We suggest that ancestors of the four extant river dolphin lineages colonized the shallow epicontintental seas that inundated the Amazon, Paraná, Yangtze and Indo-Gangetic river basins, subsequently remaining in these extensive waterways during their transition to freshwater with the Late Neogene trend of sea-level lowering.