The air missiles were launched from Russian warships in the Caspian Sea, directed over Iran and northern Iraq.
As Russian air strikes pummelled Syria, the Syrian government announced it was flushing out terrorist strongholds once and for all.
The Syrian Army's General Ali Abdullah Ayyoub announced the fresh offensive on Syrian TV.
"Today the Syrian armed forces began a wide-ranging attack with the aim of wiping out terrorist groups and liberating the areas and towns which have suffered from their crimes."
Russia says it hit 27 IS locations in Homs and Hama province and in Raqqa province in the north.
It also denied claims by an anonymous US official that four of its long-range missiles, launched from the Caspian Sea, dropped in Iran.
Russian Defence Ministry spokesman, General Igor Konashenkov, insists all cruise missiles hit their targets.
But there is increasing concern that those targets are not IS strongholds, but territory held by the US-backed Free Syrian Army in Western Syria.
Those areas include coastal plains vital to President Bashar Al-Assad and the Russians.
US State Department spokesman John Kirby says Secretary of State John Kerry expressed his disquiet in a telephone call to Russian Foreign Minister Sergei Lavrov.
"The Secretary repeated our concerns about the preponderance of targets that are being struck by Russian military forces that are not ISIL related. They also talked about the importance of moving forward on tactical discussions and dialogue towards the goal of deconfliction, again to avoid mishaps and misunderstandings, particularly in the air. And the Secretary also talked about the importance of moving forward towards a political track in Syria."
But there is no doubt civilians are yet again bearing the brunt of the conflict.
This man, believed to be in Hama province, says a Russian air strike levelled his home.
"Yesterday, the ***ing Russian plane with Assad's help, look at this. I have no home left, I have nothing left. I did not manage to get mattresses out or clothes for my girls. Look at this destruction."
"Are all your possessions gone?"
"All of it. Destroyed. Look at it. No clothes, no nothing. Look at all this destruction they have caused."
NATO ministers meeting for crisis talks in Brussels say Russia's involvement is raising tensions considerably.
NATO Secretary General Jens Stoltenberg says NATO will support its members.
"The Ministers agreed that Russia's military escalation in Syria raises serious concerns. I call on Russia to take a constructive role in the fight against ISIL.
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