At the start of Kashimashi, a young high school boy named Hazumu Osaragi declares his love to classmate and close friend Yasuna Kamiizumi, but she quickly rejects him. Dejected, Hazumu climbs Mt. Kashima and is killed when an alien spacecraft accidentally crash lands on him. To rectify this, the alien in the ship named Hitoshi Sora brings Hazumu back to life, but inadvertently regenerates him as a female right down to the DNA level. This change in Hazumu serves as the catalyst for the development of character interactions for the remainder of the series.
After Hazumu returns back to school, Yasuna unexpectedly professes her love for Hazumu, but this serves only to confuse Hazumu as she adjusts to her new life as a girl. Yasuna, a rather feminine girl, has a unique affliction which makes her incapable of seeing males, and instead sees males as covered in a gray, hazy blur. Hazumu's childhood friend Tomari Kurusu, an athletic girl and tomboy, finds Hazumu's change difficult to cope with. Tomari starts to realize her own romantics feelings for Hazumu as Yasuna starts becoming closer to Hazumu, especially after Tomari witnesses Hazumu and Yasuna kissing one day after school. A conflict arises between Yasuna and Tomari who fight for Hazumu's affection while she is unable to choose between them. This results in a love triangle emerging between the three female main characters. Hazumu's best male friend Asuta Soro also starts having romantic feelings for Hazumu, but tries his best to repress them. Tomari's good friend Ayuki Mari, an intelligent girl interested in the sciences, continuously observes the ongoing development of the love triangle while keeping a stance of watching from afar.