Ion channels regulate a wide range of physiological processes including rapid electrical signaling, fluid, hormone and transmitter secretion, and proliferation. As such, ion channels are common targets for toxins and therapeutics. Ion channel screening assays have traditionally utilized indirect or low throughput approaches. Recent improvements in sensor technologies and instrumentation have provided fresh opportunities for ion channel screening that afford higher throughput, improved information content, and access to novel ion channel targets. Ion channels subtypes can display a variety of functional differences in gating and permeability mechanisms, which necessitates use of assay technologies that selected and adapted for a specific channel type. In order to successfully implement improved ion channel screening assays that provide pharmacologically relevant data, it is critical to carefully evaluate and control a variety of assay parameters. In this chapter, we provide an overview and assessment of some of the assay technologies commonly used in ion channel pharmacology and drug discovery efforts.