A key to potassium channel activation: Using drugs to activate potassium channels has the potential to treat conditions like epilepsy, heart arrhythmias, and pain. Schewe et al. report a class of negatively charged activators (NCAs) with a defined pharmacore that use a similar mechanism to activate many types of potassium channels. X-ray crystallography, functional analysis, and molecular dynamics simulations showed that the NCAs bind below the selectivity filter to open the filter gate and activate the channels. Targeting this NCA site might be exploited in rational drug design. Science , this issue p. 875