The KCNE single-span transmembrane subunits modulate the function of voltage-gated potassium (Kv) channels, which are critical for maintaining electrical excitability and signal transduction across various tissues, by interacting with different Kv channel α-subunits to form diverse channel complexes with unique biophysical properties and regulatory mechanisms. These interactions profoundly impact physiological processes. Mutations or altered expression of KCNE genes have been implicated in a range of pathophysiological conditions. Emerging research has provided significant insights into the dynamic interactions between the KCNE gene and Kv channels, highlighting their critical roles in channel function modulation. This increasing understanding paves the way for designing novel therapeutic strategies to address ion channel-related disorders. To deepen the understanding of research advancements, this review seeks to elucidate the roles of KCNE across various organs and to provide constructive recommendations for future research.