Megumi Noda, or "Nodame" is a piano student at Momogaoka College of Music. An extremely talented pianist who wants to be a preschool teacher, she prefers playing by ear rather than reading the music score. She is messy and disorganized. Shinichi Chiaki is Momogaoka's top student. Born into a musical family, he is talented in piano and violin and has secret ambitions to become a conductor. An arrogant multi-lingual perfectionist who once lived abroad in the music capitals of the world as a young boy, he is trapped in Japan because of his childhood phobia of airplanes and the ocean. They meet by accident and sparks fly!

Ashitaka, a prince of the disappearing Emishi people, is cursed by a demonized boar god and must journey to the west to find a cure. Along the way, he encounters San, a young human woman fighting to protect the forest, and Lady Eboshi, who is trying to destroy it. Ashitaka must find a way to bring balance to this conflict.