Ion channels are an important class of drug targets. They comprise the molecular basis for essential physiological functions including fluid secretion, electrolyte balance, bioenergetics and membrane excitability. High-throughput screening for ion-channel function requires sensitive, simple assays and instrumentation that will report ion channel activity in living cells. This article will review relevant assay technologies for ion channels and describe voltage-sensitive probes and instruments based on fluorescence resonance energy transfer (FRET) that enable ion-channel drug discovery.