Manco Inca is one of Cusco history's most admired characters. His cunning and bravery have made him legendary. He broke into a meeting Pizarro was holding and proposed an alliance with him to recover the prestige and authority that had been lost by Huascar and his faction. Shortly thereafter he found that he no longer had any power, because in Francisco Pizarro's absence, Cusco was now in the hands of his brother Hernando. Due to the absence of his ally, his attitude changed, and he began to oppose the conquistadors. He was taken prisoner, but managed to outsmart his guards by offering them a human-size statue of solid gold if they would help him escape. Thus he was able to escape and organize his resistance from Vilcabamba during almost 40 years.

In 1536 Manco Inca or Manco II declared outright war against the Spanish invaders. This uprising was barely quelled by the Spaniards after the siege of Manco's headquarters.

After a grueling and bloody 8-month siege, he was finally defeated by the Spaniards and their local allies. Capitulation was inevitable, so Manco Inca dissolved his whole army enabling the soldiers to return to their families and their crops. Besides, an organized retreat under the circumstances would have been a slow one, and he had to move quickly and decisively. Thus, Manco Inca retreated to Vilcabamba, following the route of Chinchero and going through Ollantaytambo, where he obtained a small victory over the pursuing Spaniards, allowing him to form his new headquarters in the jungle.

Domination by the Spaniards was now solid. Finally, Manco Inca was assassinated in 1545 by Diego de Almagro, one of the original conquistadors. He managed to reach the presence of the rebel with a small band of followers, pretending to be deserters from Pizarro's army. They were welcomed by the Incas and were offered food and shelter, giving them the opportunity to murder the leader of the uprising.

Manco Inca was not able to pass his fighting spirit on to his son Sayri Tapac, because the latter was apparently persuaded by some Cusco family member to side with the Spanish crown. He traveled to Lima, was received by the authorities and received some lands and privileges in the present districts of Yucay, Urubamba, Maras and Chincheros. Apparently satisfied, he built an adobe palace for himself in Yucay. He died mysteriously in 1560, perhaps murdered by the quechuas who were fanning the flames of resistance to the invader.

After the death of Sayri Tapac, his brother Titu Kusi Yupanqui assumed leadership. The new Inca, who settled in Vilcabamba, recognized the political and religious committees in Cusco in order to reach an agreement with the Viceroy. In 1568 he was baptized as a Christian, but died the same year from a mysterious illness.

Then Tupac Amaru, the younger brother, young and inexperienced, but an implacable enemy of the conquistadors came to power. The Spaniards, recognizing in his rebellious character the contrast with his brother's weakness, ordered his capture. An army of almost 300 soldiers under the command of Martin Hurtado de Arbieto and Captain Martin Garcia Oņaz de Loyola was sent to do the job. They arrived in Vilcabamba searching for the Inca, but he and his family had fled to the depths of the jungle.

Finally, the last Inca was captured and taken to Cusco together with his followers by the same Garcia Oņaz de Loyola (who afterward married Beatriz Coya, niece of Tupac Amaru and heir to the Marquisette of Oropesa. After a perfunctory trial, he was sentenced to death. He was beheaded in the plaza of the Great City in Lima, in the presence of Viceroy Toledo on September 24, 1572. His remains lie in the church of Santo Domingo. Thus, the last Inca of the royal line was murdered, dousing the flame that had been kindled thirty six years previously by the warrior spirit of Manco Inca when he started the rebellion to recover the quechua nation.