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In 2019, Scafaria wrote and directed the crime comedy film Hustlers, based on a New York Magazine article from 2015, "The Hustlers at Scores," by Jessica Pressler. The film was a critical and commercial success. Scafaria said to Vox, on the real story: "There are a lot of movies that I think have touched upon these themes—The Wolf of Wall Street or movies like The Big Short—which explain [financial downturns] from the bullpen. But I’m really interesting in seeing the impact that the 2008 recession had on these women who worked in Wall Street’s backyard."

In 2015, she also directed a comedy-drama The Meddler based on her own script. The film tells the story of a mother, Marnie (Susan Sarandon), and a daughter, Lori (Rose Byrne), trying to move on with life after the loss of their husband and father. Scafaria said to the New York Times: "There’s a reason that it’s all from Marnie’s perspective because I never wanted to get a break from her. More than anything I wanted it to inspire empathy from people who might find themselves in this situation, whether it’s through loss or some other circumstance that creates strife. Once I started showing people the script, that there was something so relatable about being the adult child of someone and trying to stay best friends."

Scafaria has been in a relationship with comedian and filmmaker Bo Burnham since around 2013. They reside together in Los Angeles.

She is good friends with fellow Nick & Nora writers Diablo Cody (Juno), Dana Fox (What Happens in Vegas), and Liz Meriwether (No Strings Attached) with whom she collaborates in their writing group they call the "Fempire". In 2012, Scafaria and the "Fempire" received the Athena Film Festival Award for Creativity and Sisterhood. She wrote Iraqi war docudrama Sweet Relief for Paramount Pictures and The Mighty Flynn, a spec script which she set up at Warner Brothers. She has also written Man and Wife, which Gabriele Muccino is attached to direct.

Scafaria recorded a second record available April 1, 2010 on iTunes called "Laughter and Forgetting."

In 2009, Mandate Pictures picked up Scafaria's script Seeking a Friend for the End of the World, a romantic comedy that focused on one man's quest for a meaningful connection amid the "end of days". The film marked the directorial debut for Scafaria, and was released in June 2012. In an interview with Jan Huttner, Scafaria conveyed the depth and allure of the apocalypse concept: "Two people at the end of the world—all the chaos that's around them that they're sort of wheeling through—and obviously some people are just mowing their lawn and other people are doing heroin... But there's something to me that becomes even more romantic, and that’s what I was excited to explore and see."

During the 2007–2008 Writers Guild of America strike, Scafaria recorded a voice-and-piano album called Garden Party. The 2009 Drew Barrymore film Whip It! features Scafaria's original song "28" in the closing credits.

In early 2005, Scafaria was hired by Focus Features to adapt Rachel Cohn and David Levithan's book Nick & Norah's Infinite Playlist into a film of the same name. The screenplay was her ninth, but her first adaptation. Scafaria said to Moviemaker about the source material, "I grew up in suburban New Jersey, so I immediately identified with the characters, especially Norah. Everything from feeling uncomfortable in my own skin to having a father who’s larger than life (even if only in your mind), her plight really spoke to me and seemed like it would speak to a lot of young girls. It wasn’t hard to get inside the characters’ heads—the authors’ voices are so strong."

Scafaria was born and raised in Holmdel Township, New Jersey, the daughter of Gail and Joseph R. Scafaria. Her father was an Italian immigrant, from Gioia Tauro, Calabria. She first became interested in writing when she would write a report on a fake book once a month to win Pizza Hut gift certificates from her school. She began to take an interest in storytelling and had written and produced her first play in Red Bank, New Jersey by the age of seventeen. After graduating from Holmdel High School in 1995 she attended Lafayette College in Pennsylvania for a year before switching to New Jersey's Montclair State University when she could no longer afford Lafayette's tuition. She graduated from Montclair with a Bachelor of Arts in English with a minor in Theater.

Lorene Scafaria (born May 1, 1978) is an American screenwriter, playwright, actress, and film director. She is best known for her work on the films Nick & Norah's Infinite Playlist (2008), Seeking a Friend for the End of the World (2012), and Hustlers (2019).