The fire broke out at approximately 6:27 a.m. Wednesday on the 900 block of East 15th Street.
"On arrival, the building was well involved in fire with reports of multiple people trapped," Fire Commissioner James L. Johnson said.
There were six children in the house at the time of the blaze. Three of them live in the home and the other three were cousins staying for a visit.
The father of the kids who live in the home, Timothy Ferguson, managed to get his wife and three children out safely.
Neighbors say he desperately tried to save the others.
"The father kept screaming, 'my kids, my kids.' He kept trying to get into the front door. There was no flame, but the black, billowing smoke pushed him out again," neighbor Don Dodds said.
Firefighters rushed in and carried 4-year-old Moses McKnight who was severely burned. He was taken to Crozer Chester Medical Center in critical condition.
The bodies of the two girls were found in separate second floor bedrooms. They were Ferguson's 9-year-old daughter, Amajhay, and her 6-year-old cousin, Bella McKnight.
The family had been planning a birthday party for Amajhay this Saturday.
It was a devastating blow for Ferguson and his wife, Tyisha McKnight.
It's also been devastating for this tight knit neighborhood.
Neighbor Michael Earnest had to help restrain Ferguson from going back into the house a second time.
"You felt helpless. You felt rage. I still do. It's hard to sleep," Earnest said.
"Any fire is devastating because it puts a family out of a house, but when you lose children, it's even more overwhelming," Chester Mayor John Linder said during an afternon news briefing near the scene.
Firefighters were at the home within five minutes of the call and had the flames knocked down 10 minutes later.
Five firefighters were hurt while responding to people trapped on the second floor of the house. One was treated at the scene. The other four were taken to the hospital with minor injuries.
"They did everything they could do," Linder said.
Firefighters say there were working smoke detectors in the home.
The cause of the fire is under investigation.
Chester officials said they would post information on how to help the family on the city's website.