Bello's breakthrough came when the producers Kerry Lenhart and John J. Sakmar cast her as Mrs. Smith in the spy show Mr. & Mrs. Smith. The show was cancelled after just eight weeks on the air. Then came a guest stint on ER as the feisty pediatrician Dr. Anna Del Amico, in which she guest-starred in the final three episodes of the third season. Bello remained on the show for one season as a regular cast member, departing after the medical drama's 4th season. The actress went on into movies landing a role in Coyote Ugly. She has been nominated for the Golden Globe award twice: for Best Supporting Actress in The Cooler (2003) and for Best Actress in A History of Violence (2005). She also starred in The Jane Austen Book Club as Jocelyn.
In 2008 Bello starred in The Mummy: Tomb of the Dragon Emperor as Evy O'Connell, taking over from Rachel Weisz. Bello has stated that she has signed up for three more Mummy films.
In December 2008 Bello began developing a drama for HBO. Besides starring in the new series, Bello will also serve as an executive producer.
Bello's latest project, the 2009 Sundance film The Yellow Handkerchief, was released in theaters on February 26, 2010 by Samuel Goldwyn Films.
It was announced in 2010 that Bello will guest-star in two episodes of Law & Order: SVU.
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