The most important Spanish advances are the mission settlements, where the Jesuits Christianize native peoples.

Two areas of particular importance lie adjacent to the river systems that delimit Brazil in the south and in the north: the Parana-Paraguay Basin in the south and the Mamore-Guapore Basin in the north.

The Jesuits found eight missions among the Guaraní peoples between the Parana and Paraguai rivers in what is now southern Paraguay from 1609 to 1628.

They press deep into what is today the state of Parana, between the Ivai and Paranapanema rivers, to establish fifteen more in what is called Guaíra Province.

The Guaíra missions are attacked from 1629 to 1631 by slave hunters, known as bandeirantes, from the Portuguese town of São Paulo.

According to the governor of Buenos Aires, these attacks result in the enslavement of more than seventy-thousand Guaraní.

Consequently, the Jesuits decide to evacuate some ten thousand survivors downriver and overland to sites between the Rio Uruguai and the Atlantic, in what becomes the state of Rio Grande do Sul.