The identities of those who died is still unknown. Among those hurt, at least two suffered serious injuries.
It happened on East 187th Street between Belmont and Cambreleng avenues around 1:30 p.m.
First responders were met with heavy fire on the first floor, which rapidly raced up the stairs, spreading to all floors of the five-story building.
The building is home to a barbershop and deli on the ground floor as well as six apartment units on floors two through five.
FDNY officials say firefighters extinguished fire on the first floor fours, but when they hit the top floor, the roof collapsed throughout a large portion of the building, as did part of the stairwell.
FDNY gives updates on deadly Bronx building fire
Firefighters then moved to exterior operations, and rescued several people in the back and front of the building, including a civilian who had to be rescued by firefighters from a window via a ladder. Several others were rescued from a fire escape.
"56 truck rescued a civilian trapped in a window with no access to a fire escape and rescued that victim via portable ladder," said FDNY Chief of Operations Kevin Woods.
Luciano Silva, who escaped the burning building, scrambled out of a first-floor apartment and managed to get his dogs, but his skittish cat ran.
Alex Reyes and his brother managed to grab their cat when they smelled the smoke.
"I looked down and there was fire on the first floor," Reyes said. "He grabbed the cat bag. We put the cat in the bag. He was like, 'let's take the stairs.' I was like, 'we ain't taking no stairs.' You can see the black smoke going through the door."
They took the fire escape from the fourth floor.
Many other residents were at work or school.
"I'm in high school," said Sharell Rojas, who lost everything. "I only have my phone on me, and the clothes that I have on now."
Upwards of 250 firefighters and EMS personnel worked to bring the five-alarm fire under control just after 6:30 p.m.
Unfortunately, officials say two people were killed, two suffered serious injuries, four civilians suffered minor injuries and five firefighters also suffered minor injuries. They were taken to local hospitals.
"If not for their heroic efforts, there would have been many more serious injuries and potentially fatalities," Bronx Borough President Vanessa Gibson reacted.
Residents wonder what comes next with structural concerns eliminating hope of a return to their homes.
The Red Cross has registered 23 households, including 24 children and 53 adults, so far.
There's no word yet on what caused the fire.
Fire marshals are working around the clock to determine what caused the deadly blaze.
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