Nazir had survived several assassination attempts including at least two previous American drone strikes.
In November, a suicide bomber tried to kill him as he was arriving at an office where he used to meet with local residents and hear their complaints. Nazir and more than a dozen other people were wounded in the attack, and seven were killed.
No group claimed responsibility, but suspicion immediately fell on rival militants including the head of the Tehrik-e-Taliban (TTP), Hakimullah Mehsud, who had been jockeying with Nazir for power in South Waziristan. The TTP is an umbrella group of militants formed to oust the Pakistani government and install a hardline Islamist regime. They have been behind much of the violence tearing apart Pakistan in recent years.
Nazir's non-aggression pact with the Pakistani military allowed the army to launch a massive operation in South Waziristan against the TTP which displaced more than 800,000 people and drove Hakimullah Mehsud from the region.
In retaliation for the assassination attempt, Nazir expelled members of the Hakimullah's Mehsud tribe from Wana. Nazir was meeting with supporters to discuss how to deal with the TTP when the missiles struck on Wednesday night, said Mehsud from the FATA center.
Nazir's group quickly appointed his close aide Bawal Khan as a replacement, according to one of Nazir's commanders. He spoke on condition of anonymity because he was not authorized to talk to the media.
But it remains to be seen what the new leader's policies will be and whether the tension with the TTP could lead to a power struggle in the region.
"Trouble will follow," said Mehsud.
The former chief of intelligence in northwest Pakistan, retired brigadier Asad Munir, said Nazir's killing will complicate the fight against militants in the tribal region, and could prompt Nazir's group to carry out retaliatory attacks against the Pakistani army in South Waziristan.