Their homeland has been called the "hidden Darfur," where some 350,000 people have been driven from their homes into the jungles or refugee camps in neighboring Thailand.
Now, many of the survivors are pinning their hopes on a historic election November 8 pitting the military-backed ruling party against one helmed by pro-democracy icon Aung San Suu Kyi and numerous ethnic parties.
They fear victory by the military's United Solidarity and Development Party would plunge Karen state and its 1.5 million people back into a hellhole.
Ethnic minorities including the Karen make up about 40 percent of Myanmar's 52 million people. For them, the election is more than a step in Myanmar's uneven path toward democracy.
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It opens up the possible fulfillment of a long-cherished dream.
Shortly after the country, then known as Burma, gained independence from Britain in 1948, the Karen rose against the central government, which then and since has been dominated by the Burman ethnic majority.
All promises were broken following a 1962 military coup, after which a welter of insurgent groups from the Kachin, Shan, Karen and other minorities rose up in revolt.
Myanmar historian and government adviser Thant Myint-U has called this endless, bloody struggle the country's "original sin."
"Myanmar will not be able to fulfill its potential, or provide the kind of future its people expect and deserve, without finding a lasting resolution to the ethnic conflicts it faces," says Tim Johnston, Asia director for the think tank International Crisis Group.
But only eight of the more than 20 armed groups signed it, including the Karen National Union (KNU), the minority's main insurgency group. Other ceasefires were negotiated in the 1980s and '90s, only to be violated.