The US has accelerated the rate of attacks in Pakistan's tribal belt since Barack Obama came to power, but the secret programme is deeply unpopular among Pakistanis and blamed for hundreds of civilian deaths.
While more than 1900 insurgents have been killed by American drones since 2006, according to The Long War Journal, residents say they live in fear of getting caught up in the strikes.
"The drone attacks are targeting innocent people, innocent women and children," Malik Shahzada told about 1500 people gathered in Miranshah, the main town of North Waziristan, an area known to harbour terrorist gangs and militant fighters.
Residents declared a general strike and said they would attack Pakistani forces if the government did not the US strikes.
With Pakistan dragging its feet on a major ground offensive to clear the militant havens in North Waziristan and with the US unable to deploy troops, the drones are considered critical in seeking out and destroying bases used by the Haqqani network and other al-Qaeda-linked groups.
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Baitullah Mehsud, leader of the Pakistan Taliban, was killed by a drone attack in 2009 and Ilyas Kashmiri, a senior al-Qaeda commander, is believed to have been killed this month even as he plotted attacks to avenge the death of Osama bin Laden.
US officials believe the success of the remote-controlled drones may allow a more rapid withdrawal of forces from Afghanistan But such is the sensitivity in Pakistan, that the US has agreed to keep the CIA programme secret in order not to embarrass the government in Islamabad.
Meanwhile the Pakistani government has repeatedly condemned the strikes in public, while privately telling the US it has the green light – an accommodation revealed in diplomatic cables released by WikiLeaks last year.
Today the US and Pakistan relationship looks ever more fragile, and there are fresh calls to halt the drone strikes in order to reassert Pakistani sovereignty following the US raid to kill Osama bin Laden.
A senior Pakistani security source told The Daily Telegraph: "Drones are something that we cannot allow."