In 1999, she portrayed the girl on a sinking sailboat in Message In A Bottle.
She played the role of Coach Yoast's daughter, Sheryl, in the 2000 Disney film Remember the Titans.
Thanks to her role on Heroes, she became a regular on the science fiction convention circuit, invited to attend conventions around the world in 2007, including Gen Con, New York Comic Con, and Fan Expo Canada.
Panettiere has complained that her acting options are sometimes limited because "people look at [her] as either the popular cheerleader type or just the blonde".
While on Guiding Light, Panettiere's character Lizzie battled leukemia.
For drawing the attention of daytime viewers to the disease, and for improving national awareness, the Leukemia & Lymphoma Society gave her its Special Recognition Award.
In 2004, Panettiere had her first starring role in the Disney Channel film Tiger Cruise.
Panettiere became most prominent as Claire Bennet in the NBC series Heroes, which was created by Tim Kring, as a high school cheerleader with regenerative healing powers.
In April 2011, Panettiere appeared in the Scream sequel, Scream 4, playing Kirby Reed, a role for which she received acclaim and was considered to be a highlight of the film, which received mixed reviews. In 2012, The Forger, in which she played the role of Amber, was released direct to DVD (both this and Hoodwinked Too! Panettiere voiced Kairi in Kingdom Hearts and Kingdom Hearts II.
The same year she replaced Anne Hathaway as the voice of Red for the animated sequel Hoodwinked Too! While she was replaced by Alyson Stoner in Kingdom Hearts Re: Chain of Memories and Kingdom Hearts 358/2 Days, she reprised her role in Kingdom Hearts Birth by Sleep and also voiced Xion in Kingdom Hearts 3D: Dream Drop Distance.
Panettiere's first single, "Wake Up Call", was digitally released on August 5, 2008.
The clothing brand Candie's announced that it was premiering an ad campaign for the single in late July.
ABC canceled the series in May 2016 but it was later picked up by CMT and Hulu for a fifth season.