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The story of Eyeshield 21 follows the protagonist Sena, the whipping boy of his classmates, who wants to earn respect by joining a club at the start of the school year. He crosses paths with Hiruma, head of the American soccer club, who recruits him for his exceptional running skills. They must quickly find 11 other players, as the inter-school championship begins in 24 hours.

Numerous artists and composers were involved in creating the theme music and accompanying songs, including Kosuke Morimoto, who contributed to various theme songs for Fullmetal Alchemist and One Piece. Any fan of the series will have a strong feeling of nostalgia when they recall the music that marked them during their teenage years. The very Pop-rock and J-pop tones will remind them of those after-school afternoons watching episodes of this epic anime on Game One. You'll also be able to hear the voices of the Japanese cast, including the voice of the main character, Sena Kobayakawa, on many of the credits and accompanying songs.

The manga turns 21 in 2023. To celebrate, the author wrote a 55-page one-shot called "Brain X Brave", which appeared in early January 2024 in Weekly Shonen Jump. The anime has been broadcast frequently on Game One since September 2009 and on France Ô since September 2012.