KCNQ potassium channels play a critical role in controlling membrane excitability.Like a typical voltagegated ion channels (Kv), KCNQ channels undergo closed to open transitions by sensing transmembrane potential changes and mediate inhibitory potassium currents.Reduction of KCNQ channel activity as results of genetic mutation is causal to a variety of human diseases including epilepsy, arrhythmia and deafness.Hence, discovery of small compounds to activate voltage-gated ion channels is an important strategy for clinical intervention in human diseases caused by membrane hyperexcitability, including anxiety, epilepsy, arrhythmia and neuropathic pains.Because the binding of these molecules induces a conformational change leading to the opening of these channels, there is also a considerable conceptual interest in understanding the molecular basis of these "gain of a function" molecules.Small molecule activators of cation channels are rare; however, several novel compounds have been identified for KCNQ potassium channels.Recently, we reported two new molecules which potentiate either cardical or neuronal KCNQ channels and identified molecular determinants for their activity, which provide exciting insights into activation of voltage-gated channels by small molecuars.