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In the last centuries before the Spanish conquest, numerous small warrior kingdoms (señoríos) arose in and around Tlaxcala. Some of them formed a loose federation that remained independent of the Aztec empire as it spread from the Valle de México in the 15th century. The most important kingdom seems to have been Tizatlán, now on the northeast edge of Tlaxcala city.

When the Spanish arrived in 1519, the Tlaxcalans fought fiercely at first, but ultimately became Cortés’ staunchest allies against the Aztecs (with the exception of one chief, Xicoténcatl the Younger, who tried to rouse his people against the Spanish and is now a Mexican hero). The Spanish rewarded the Tlaxcalans with privileges and used them to help pacify and settle Chichimec areas to the north. In 1527, Tlaxcala became the seat of the first bishopric in Nueva España, but a plague in the 1540s devastated the population and the town has played only a supporting role ever since.