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Since the mid 17^th Century, with the drastic decrease in the indigenous population of the Lower Amazon, as a result of slavery and epidemics of yellow fever, there was an enormous need for manual labor for work on the ranches and in the harvesting of “backland drugs” [i.e., spices, etc.]. The colonists and missionaries of São Luís and Belém thus were led to make incursions into the backlands of the Rio Negro and Amazon, capturing Indian slaves and massacring those who resisted: these were the “ransom troops” and the “just wars". The Fort of Barra de São José do Rio Negro (where today the city of Manaus is located), built in 1669, served as a base for future expeditions in search of slaves.

In the first half of the XVIIIth Century, after the defeat of the Manao and Mayapena, who dominated the Lower and Middle Rio Negro and who had previously collaborated with the Portuguese in obtaining slaves, the Portuguese reached the region of the Upper Rio Negro and its principal tributaries, the Uaupés, Içana andXié, which were still densely populated and practically not affected by the Whites. In this period, the Carmelites established settlements up to the Upper Rio Negro, in the vicinity of the present-day city of São Gabriel da Cachoeira. The commerce in slaves became so intense in the 1740s that it was estimated that by the mid-XVIIIth Century, around 20 thousand Indians had been taken prisoner and made to descend the Upper Rio Negro. Unknown numbers of slaves were also taken by private slavers who worked independently of the official slave trade. In the official lists of slaves removed from the region, are included a large number of Tukano, Baniwa, Baré, Maku, Werekena and others who today live in this same area, brought to work in Belém and São Luís.

As a result of the contact with the Portuguese, a smallpox epidemic devastated the Upper  Rio Negro in 1740, killing a large number of Indians, for it is quite probable that it may have spread through parts of the region where no direct contact had been made with the “whites”, by means of cotton cloth and clothes. Between 1749 and 1763, recurrent epidemics of smallpox and measles repeatedly swept the region, the measles epidemic of 1749 being so terrible that it came to be called “big measles".

The most famous indigenous revolt of this period was that of 1757, led by the chiefs of the town of Lamalonga on the Middle Rio Negro. This rebellion marks the revolt of the Indians against the missionaries, which is attested by the destruction of the chaples and religious paraphernalia and the killing of a Carmelite priest.

In the second half of the XVIIIth Century, the Portuguese government under the direction of the Marquês de Pombal removed the “temporal power” of the missionaries. They lost control over the administration of the villages, which were then put under the administration of the colonists, civilians or military, who also were given the title of “Directors of the Indians". The missionaries were, nevertheless, authorized to stay in the villages to go on with the work of catechization and persuasion of the Indians at the headwaters of the rivers and streams to come downriver and settle in the villages of the middle and lower Rio Negro. Even so, there was a notable decline in the missionary work. The most prosperous villages were promoted to the category of towns, and were given Portuguese names, which were often saint names. The decrees of the Marquês de Pombal sought to put an end to slavery and promote the assimilation of the Indians into colonial society.

The Marquês de Pombal wished to grant to the Indians the same rights as the Europeans, but he soon understood that the colonists depended for their survival on indigenous labor, both in agriculture and in the extraction of forest products. He established a system of labor in which part of the men in good health would work for several months a year on the building of houses in the colonial towns, while others would take care of the plantations. But this system of labor organization was not respected and the Indians continued to be exploited by the colonists. Hundreds of them were taken to the colonial towns during this period.

With a base in the forts built in 1763 (São Gabriel and São José de Marabitanas), Portuguese military explorers made exhaustive journeys over the upper tributaries of the Negro, a strategic region due to its location on the borderlands between the Portuguese and Spanish colonial empires, especially after the signing of the Treaty of Madrid in 1750.

For the indigenous peoples, this period meant the near complete opening of their territory by the Portuguese military, and also the increase in depopulation of the villages as a result of the “descents”, a veiled form of slavery which put the Indians to work on the boats and on agriculture. The costs of this policy for the Portuguese were high, for it provoked numerous revolts and desertions of the settled Indians, and the constant necessity of replenishing the labor force necessary for the production of indigo and manioc and the gathering of cacao.