Assad's troops, backed by battle-hardened Lebanese Hezbollah fighters and emboldened by their capture of a strategic border town, are starting an offensive to regain the rebel-dominated north and remaining rebel strongholds around Damascus.
The pro-opposition Syrian Observatory for Human Rights said the rebels had seized an army checkpoint on the Ariha-Latakia stretch of an international highway that goes through Syria's biggest city, Aleppo, to the Turkish border.
Other rebel groups said opposition forces had seized three checkpoints and needed to capture three more to cut off army access to the M5 highway.
"This is a very important battle in our move to put a stranglehold on regime supply lines from its stronghold on the coast into the north, particularly to Idlib city, which is one of the regime's last footholds in Idlib province," said Mohammed Fizo, a rebel spokesman speaking by Skype.
"The regime is responding by shelling the highway and sending fighter jets to bomb nearby villages."
Assad's forces aim to retake Aleppo, where they have been mired in a bloody stalemate with rebels for nearly a year.
World powers remain at odds about how to handle the Syrian crisis, which dominated the Group of Eight conference this week but led to no political breakthroughs. The United States wants Assad removed and has promised to arm the rebels, while Russia, the Syrian leader's main arms supplier, opposes these policies.
Their disagreements have complicated their joint efforts to bring the Syrian government and opposition together for proposed "Geneva 2" peace talks, now not expected to start before August.
Assad's military offensive aims to strengthen his hand in any negotiations, but his forces face a tough task in the north, where rebels hold swathes of territory, some adjacent to Turkey, which backs them and lets weapons and supplies cross the border.
Rebel spokesman Fizo said rebels had been working to isolate army checkpoints along the highway in Idlib for months. If they successfully seized the road, they would then move on to the army's secondary supply route further north.
Rami Abdelrahman, head of the British-based Observatory, said that a successful rebel campaign could sever all ground supply routes into northern Syria from the Mediterranean coast, where many of Syria's most fortified military sites are located. The coast is home to many minority Alawites, whose sect is an offshoot of Shi'ite Islam and who form Assad's core support group.
In the port city of Latakia, part of Assad's coastal stronghold where rebel attacks have been rare, opposition and state media said an arms store on a military site had exploded.
State television said the blast was caused by a technical fault and had wounded six people. The Observatory said 13 soldiers had been hurt, some of whom were in critical condition. It said the cause of the blast was still unclear.
Syria's 27-month-old conflict began as a protest movement against four decades of Assad family rule, but has evolved into a civil war that has killed more than 93,000 people.
The violence risks splitting Syria between Alawites, Sunni Muslims and Kurds, and igniting a regional conflict as Hezbollah and Iraqi Shi'ite fighters join Assad's forces and foreign Islamist militants line up with mostly Sunni Syrian rebels.
A Syrian rebel unit claimed responsibility in a video for killing four Shi'ite men in Lebanon this week, saying they were Hezbollah fighters trying to enter Syria.
When Assad's forces captured Qusair, in central Homs province near the Lebanese border, earlier this month, they had the support of Lebanese Shi'ite towns loyal to Hezbollah.
Want to enjoy 'Zen' reading - with no ads and just the article? Subscribe todaySubscribe now