April Kepner was introduced in the episode "Invasion" as a former surgical resident at Mercy West Hospital who joins the staff at Seattle Grace Mercy West after the two hospitals merge.

Much of her background is revealed in the episode "Death and All His Friends." While being held at gunpoint by Gary Clark, she tells him about her life in an attempt to convince him not to shoot her, a technique she says she learned from watching Oprah. She was born on April 23 and grew up in Columbus, Ohio. Her mother Karen is a teacher, and her father Joe is a corn farmer. She is the second of four daughters; her sisters are Libby, Kimmie, and Alice.

Following the shooting, April and Jackson Avery move in with Meredith, who also lives with Derek, Lexie, and Alex Karev. April and Meredith become closer in season seven, prompting a jealous outburst from Meredith's sister Lexie. April reveals that she is a virgin because she wants the first time she has sex to be special. The other surgical residents make fun of her, but she advises them not to judge her, as she does not judge them.