Police said a man, woman and two young children were found dead in the home.
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The two young children are 4-year-old twin boys, sources told the ABC San Francisco affiliate KGO I-Team.
"Unfortunately, we located four deceased people inside the home - one adult male, one adult female and two children," said Jerami Surratt, public information officer with the San Mateo Police Department.
Residents said this is a quiet, suburban, safe neighborhood. They never thought something like this would happen.
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"Streets closed between 41st and 42nd, and I am going, 'that is my area,'" said Donnita McDevitt, who was on a routine walk around the block when she saw the police tape. "It is quiet, safe, I walk it every other day at least, and this breaks my heart."
Never did she think her almost daily walks would involve being near a crime scene.
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"This is just not the norm for this area. I mean it has turned out to be a crazy world out there now, but this in our area of Westwood Knolls? No no," she said.
Resident Bob Mateus grew up in the area.
"It's terribly tragic; we don't have anything like that. I grew up here," Mateus said.
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Ronna McMurray said she walks by that house every night.
"We can only assume what has happened - whatever has happened - is a major tragedy, and you wonder what could've been done to avoid it," McMurray said.
Investigators had the road blocked off for most of the day.
Police could not say if a weapon was involved or recovered.
No further information about cause of death was available, but police investigating the scene said there was no sign of forced entry, and this was an isolated incident.
Investigators said they are not looking for any suspects.