We highlight the therapeutic potential of Kir4.1 channel modulators in brain diseases, specifically Kir4.1 channel stimulators (e.g., channel activators and expressional enhancers) for epileptic disorders and other diseases such as Huntington’s disease and neuropathic pain, and Kir4.1 channel inhibitors (e.g., channel blockers and expressional suppressors) for depressive disorders and autism (Figure 4). Here, KCNJ10 is linked to depressive disorder.