That year the Jesuit superior of the Tarija College, José Francisco de Arce, led an expedition to a Chiquitos settlement a few days’ ride north of the boomtown of Santa Cruz to found the reduction of San Javier on December 31. He went when he heard that a smallpox epidemic had struck the peaceful indigenous peoples who occupied the vast region east of Santa Cruz between the Paraguay and Guapay rivers, sandwiched between the Gran Chaco and Brazil. The name Chiquitos (little ones) had been given to the 31 tribes in this area by the sixteenth-century explorer Ñuflo de Chávez as a reference to the narrow doors of their homes. Although the Jesuits had tried to missionize the Chiquitos as early as 1587, when Frs. Martínez and Samaniego worked with them out of Santa Cruz, they had little sustained contact with the tribes until Arce’s expedition at the end of the next century.

The Jesuit provincial of Paraguay had hoped to improve upon the usual route between the colonial cities which went far out of the way, via Tucuman (in modern-day Argentina) and Tarija (in Bolivia). Nevertheless, this new colonial road was not to be. All of the Jesuits who attempted exploratory expeditions were slaughtered by the hostile Payaguá Indians who lived between Asunción and the Chiquitos territory, including Arce himself in 1715. Throughout colonial history, the Chiquitos missions would remain hemmed in by hostile tribes and the swamps of the Pantanal, inaccessible on all sides except for the lifeline to Santa Cruz. This isolation continues to this day.