The FBI director said there is no indication so far that the alleged shooters were part of a larger organized group, cell or network.
Comey said there was no contact of significance between either shooter and anyone under investigation by the bureau.
"There was nothing about the contact between either of these killers and our subjects that brought these killers onto our radar screen," he said.
He said the FBI is trying to be thorough and thoughtful, trying to understand the motives of the suspects and details of their lives, because "there's a lot of evidence in this case that doesn't quite make sense."
In the hours just before Wednesday's attack the female member of the suspected attackers, using an alias, swore allegiance to ISIS leader Abu Bakr al-Baghdadi on Facebook, according to law enforcement officials.
While the FBI would not discuss the post in details, sources privately expressed great concern that the attacks are an indicator that ISIS’ influence inside the U.S. through an unprecedented social media campaign has now resulted in deadly consequences.
"The internet offers the ability for people to consume poison and radicalize entirely in private, either through a device they're holding in their hands or inside their house," said Comey.
Comey urged the public to notify law enforcement if they see something that seems out of the ordinary.
"We investigate in secret, so that we don't smear innocent people," Comey said.
Attorney General Loretta Lynch, who spoke alongside Comey, pointed out that the investigation was still "evolving."
Suspects Tashfeen Malik and her husband, Syed Farook, were identified by police as the two shooters in the San Bernardino attack that left 14 people dead and 21 others injured Wednesday.
Not long before Comey and Lynch briefed reporters, David Bowdich, FBI assistant director in charge of Los Angeles, said the agency is officially investigating the shooting massacre as an "act of terrorism" after it determined there was "extensive planning" involved with the attack. The San Bernardino Police Department also handed over the lead investigation to the FBI.
“There’s a number of pieces of evidence that has pushed this off the cliff," Bowdich said at a news conference this afternoon in San Bernardino. "We do hope that the digital fingerprints that were left by these two individuals will take us towards their motivation. That evidence is incredibly important."
He noted that investigators had found two broken cellphones that they believe show Malik and Farook were actively trying to cover their tracks.