From 2008 to 2009 she starred as Dr. Daria Wade in the series ER. Shiri starred as Cate Cassidy in the TV series Life Unexpected from 2010 to 2011. In 2012 she starred as Lucy in the series Dating Rules from My Future Self. From 2012 to 2013 she starred as Clarice in Chicago Fire. She starred as Rachel in 2014 in the series Un-Real and as Natalie in the series Girls from 2013 to 2014. Appleby has also starred in a variety of movies, including I Love You toe Death, Family Prayers, The Other Sister, The Thirteenth Floor, Deal of a Lifetime, A Time for Dancing, Swimfan, The Battle of Shaker Heights, Undertow, When Do We Eat?, Havoc, I-See-You.com, I’m Reed Fish, The Killing Floor, What Love Is, Charlie Wilson’s War, and Love Like Wind. She has been nominated for a Teen Choice Award, Young Artist Award, and Online Film & Television Award.