Voltage-gated potassium channels are important determinants of membrane excitability. This family of ion channels is composed of several classes of proteins, including the pore-forming Kvalpha subunits and the recently identified auxiliary Kvbeta subunits. A combination of a large number of genes that encode various alpha subunits and beta subunits and the selective formation of alpha-alpha and alpha-beta heteromultimeric channels provides rich molecular diversity that allows for regulated functional heterogeneity in both excitable tissues and nonexcitable tissues. Because the Kvbeta subunits can either upregulate or downregulate potassium currents, depending on the specific subunit combination, it is essential to understand their function at the molecular level. Furthermore, targeted changes of the Kvbeta expression or disruption of certain alpha-beta interactions could serve as a molecular basis for designing drugs and therapy to regulate excitability clinically.