But it's unlikely that Assad will step down to end his family's 42-year dictatorship, which is rooted in the minority Alawite Muslim sect and has subjugated the mainstream Sunnis who comprise 75 percent of the population.
The dead include Defense Minister Gen. Daoud Rajiha; Maj. Gen. Assef Shawkat, the deputy defense minister and former chief of Military Intelligence who was married to Assad's sister Bushra; and Lt. Gen. Hassan Turkmani, deputy vice president and former defense minister considered a key Assad strategist.
State officials confirmed the deaths and said Intelligence chief Hisham Bekhtyar and Interior Minister Mohammed Ibrahim al-Shaar were wounded.
The assassination of such high-ranking figures may well prove to be a turning point in the revolution but the initial indications are that Assad and his lieutenants will tough it out.
Wednesday's bombing of the national security headquarters, one of the most heavily guarded buildings in Damascus, a few blocks from Assad's palace, could further undermine the power elite surrounding him.
In recent days, it's been badly hit by a series of high-profile defections.
The most significant is Brig. Gen. Manaf Tlass, a Sunni whose family has long been a pillar of the Alawite regime, defected last week, possibly with the connivance of French intelligence personnel. He's now in Paris.
Tlass, who commanded a brigade of the ultra-loyal Republican Guard, is a potential new leader of the rebel forces, although his family's complicity with the regime over the years could prevent that.
However, French Foreign Minister Laurent Fabius says Tlass, whose father was the long-serving defense minister under Assad's late father Hafez, has been in touch with the Syrian opposition.
The family of Maj. Gen. Rustom Ghazali, head of Military Intelligence's Branch 227 which has spearheaded the regime's brutal crackdown on the mainly Sunni opposition, was reported to have defected to Jordan several days ago.
Ghazali, or someone claiming to be him, denied that in a telephone interview with the pro-Assad Addounia TV channel.
But a senior source in the Free Syria Army, the rebels' main military force, insisted the Ghazali, 59, had himself defected after the regime tried to kill him.
Several Syrian ambassadors have also jumped ship and Turkey's foreign ministry reported Wednesday that two Syrian brigadier generals and several colonels were among a group of officers who crossed into Turkey Tuesday night.
Initial reports said Wednesday's attack was carried out by a suicide bomber.
There were indications later that the rebels had apparently been able to penetrate Assad's security apparatus to plant the bomb, made of TNT and military-grade C4 explosives, in the room where the high-ranking officials were meeting, and detonate it by remote control.
Either way, the rebels' infiltration into one of the most secure buildings in the capital marks a major blow for the regime as it faces an increasingly militarized opposition and holds out the possibility of more such bombings.
In the last few days, the FSA and other rebel units have for the first time fought pitched battles with Assad's regime in the heart of the capital, another blow to the regime's claim it's fighting foreign-backed "terrorists and criminal gangs."
Wednesday's bombing, and five later attacks in Damascus that apparently targeted intelligence offices and other symbols of state control, underlined how the long-disparate rebel forces are becoming more unified and better armed, largely due to weapons funded by Saudi Arabia and Qatar.
Some analysts say the rebels have achieved something approaching a balance of military capability with the regime, although they remain heavily outnumbered and outgunned by Assad's largely Alawite loyalists.
Indeed, Israel's, Military Intelligence reports that Assad is withdrawing troops from the Golan Heights, half of which is occupied by the Jewish state, to bolster his forces in Damascus.
Despite the defections, the army and the security services remain largely intact and show no obvious sign of abandoning him.
Until that changes, the regime, backed by its longtime ally Iran and Russia and China in the U.N. Security Council, will likely be able to hold on.
But more bombings like Wednesday's, stabbing directly at the heart of Assad's embattled regime, could significantly deepen its isolation and encourage other key figures to get out.
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