Linguistic, archaeological, and mythological evidence suggests that from at least 3500 B.P. Northern Maipure speakers occupied the upper Rio Negro/upper Orinoco Valley, where they encountered forest-dwelling and nomadic Maku peoples. By the time of first European contact in the mid-sixteenth century, this region was inhabited by a diversity of Northern Maipure-speaking groups. From mid-eighteenth-century sources, it can be determined that to the north and northwest of the Waukuenai were the Piapoco, Guaypunaves, Warekena, Baniwa, and Puinave; to the northeast and east were Bare, Warekena, and Yavitero; to the southeast were Bare, Maipure, and Manao; to the south and southwest were Tariana, other Arawakan, and Tukanoan-speaking peoples; and to the west were Tukanoans and probably Cariban-speaking peoples. Wakuenai oral histories of their relations with other Arawak and Tukanoan peoples indicate shifting patterns of war making and alliance.
Fairly continuous contact with Europeans dates from the mid-eighteenth century, when the Portuguese and Spanish slave trade penetrated the upper Rio Negro/Orinoco, resulting in the intensification of intertribal warfare and severe tribal depopulation. Despite their losses, the Wakuenai appear to have remained relatively populous and may have absorbed renegades of the slave wars from other tribes. Following the abolition of Indian slavery in 1755, numerous Wakuenai were settled in colonial villages of the Rio Negro, where they came to form part of the caboclo (mestizo) population. Diseases and unstable conditions led many to return to their homelands at the end of the eighteenth century, where they attempted to reorganize their society. In the early nineteenth century Brazilian and Venezuelan traders began working among the Wakuenai and, often in alliance with the frontier military, exploited Indian labor. Their abuses became extreme by the 1850s, and growing Indian resistance culminated in a series of millenarian movements in 1857-1858, led by the Wakuenai prophet Kamiko, whose influence lasted for nearly forty years and extended to various tribes of the region.
By the 1870s the rubber boom reached the upper Rio Negro, intensifying exploitation of Wakuenai labor by White employers. Abuses by the frontier military at the beginning of the twentieth century, coupled with epidemic diseases, caused the Wakuenai to live under a virtual reign of terror. In the 1940s Protestant evangelism, introduced by the North American New Tribes Mission, stimulated a new wave of millenarian movements among the Wakuenai of Venezuela, Colombia, and Brazil. With the later installation of Catholic missions on the Içana, religious allegiances became seriously divided. Encroachments by gold panners and mining companies, as well as military projects to control the frontiers, have divided the Wakuenai even more, although these pressures have stimulated new forms of political organization focused on defending their land, resources, and culture.