In the worst days of the war, attacks shook the capital, Bogota, which rebels threatened to overrun, and battles between the guerrillas, paramilitaries, drug gangs and the army raged in the countryside, parts of which remain sown with landmines.
Thousands of civilians were killed in massacres, especially in rural areas, as the warring sides sought to prevent people from collaborating with or supporting enemy forces.
Despite widespread relief at an end to the bloodshed and kidnappings of the past 52 years, the deal has caused divisions within Latin America's fourth-largest economy.
Former President Alvaro Uribe and others are angry the accord allows rebels to enter parliament without serving any jail time.
In Cartagena on Monday, huge billboards urged a "yes" vote in the referendum, while Uribe led hundreds of supporters with umbrellas in the colors of the Colombian flag urging voters to back "no."
The FARC, or Revolutionary Armed Forces of Colombia, which began as a peasant revolt, became a big player in the cocaine trade and at its strongest had 20,000 fighters. Now, its some 7,000 fighters must hand over their weapons to the United Nations within 180 days.
Colombians are nervous over how the rebels will integrate into society, but most are optimistic peace will bring more benefits than problems.
"This is the moment, it's now or never," said 50-year-old lawyer Melquis Pulecio, as he watched the ceremony with thousands of others on a big screen in central Bogota. "We are tired of this war - we were born to war."
Colombia has performed better economically than its neighbors in recent years, and peace should reduce the government's security spending and open new areas of the country for mining and oil companies.
But criminal gangs may try to fill the void in rebel-held areas, landmines hinder development and rural poverty remains a huge challenge.
With peace achieved, Santos, a member of a wealthy Bogota family, will likely use his political capital to push for tax reforms and other measures to compensate for a drop in oil income caused by a fall in energy prices.
"It's such an important day," said Duvier, a nom de guerre for a 25-year-old rebel attending a FARC congress last week in the southern Yari Plains that ratified the peace accord. "Now we can fight politically, without blood, without