She was 71.
Ephron died Tuesday surrounded by relatives at a New York hospital, where she was undergoing treatment for acute myeloid leukemia, her family said in a statement.
She wore many hats: essayist, playwright, journalist, novelist, an Oscar-nominated screenwriter and a movie director.
An accomplished screenwriter, her romantic comedies featured strong but appealing characters who tackled relationship issues with a comic insight into their situations.
They included box office hits "When Harry Met Sally" and "Sleepless in Seattle," both of which earned her screenwriting Oscar nominations.
She also received an Oscar nomination for "Silkwood," the story of anti-nuclear activist Karen Silkwood.
"An amazingly talented girl who was able to accomplish everything she set her mind to with great style and will be missed enormously," actor Martin Landau said in a statement.
Ephron also wrote and directed "Julie & Julia," which earned Meryl Streep a best actress Oscar nomination in 2010.
"What a loss. A magnificent spirit and voice. She changed romantic comedy forever," actress Debra Messing said.
Ephron was born on May 19, 1941, into a family of writers.
Her parents, Henry and Phoebe Ephron, wrote screenplays for "Carousel," "Desk Set" and "There's No Business Like Show Business."
While her parents' works live on through movie rentals and classic film channels, perhaps the elder Ephrons' true legacy is their daughters.
Nora Ephron made her directorial debut with the 1992 comedy, "This Is My Life," which she co-wrote with her sister, Delia.
Both sisters also put together a production fashioned around Ilene Beckerman's best-selling book "Love, Loss and What I Wore."
Ephron believes her parents' humor was a big part of her productions.
"They were funny and they believed that everything was copy," Ephron said in 2009. "They believed that anything in life could be turned into a story, which is really the first rule of humor. I don't think you can get through almost anything without humor."
She married screenwriter Nicholas Pileggi in 1987, eight years after she divorced investigative reporter Carl Bernstein. Her failed marriage to Bernstein was the basis of her book and movie, "Heartburn."
"I feel bad for the people who don't at some point understand that there's something funny in even the worst things that can happen to you," Ephron said.
New York City Mayor Michael Bloomberg said Ephron's stories set in his city are classics.
"You've Got Mail" and "Sleepless in Seattle," her romantic comedies starring Tom Hanks and Meg Ryan, were among her movies that featured a lot of the city's iconic buildings as a backdrop.
"The loss of Nora Ephron is a devastating one for New York City's arts and cultural community," Bloomberg said in a statement. "From her earliest days at New York City's newspapers to her biggest Hollywood successes, Nora always loved a good New York story, and she could tell them like no one else."
In addition to making movies, Ephron also tackled writing in many other forms. Her essays include "I Remember Nothing" and "Crazy Salad." She also wrote the 2002 play, "Imaginary Friends."
Three years ago, Ephron provided a list of some of the best advice she's ever got.
It included "life is too short" and "location, location, location," an appropriate sentiment for a director whose romantic comedies focused on seizing the moment in major metropolitan cities.
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