Ion channels are targets of many therapeutically useful agents, and worldwide sales of ion channel-targeted drugs are estimated to be approximately US$12 billion. Nevertheless, considering that over 400 genes encoding ion channel subunits have been identified, ion channels remain significantly under-exploited as therapeutic targets. This is at least partly due to limitations in high-throughput assay technologies that support screening and lead optimization. Will the recent developments in automated electrophysiology rectify this situation? What are the other major limitations and can they be overcome? In this article, we review the status of ion channel drug discovery, discuss current challenges and propose alternative approaches that may facilitate the discovery of new drugs in the future.