Drugs acting at the cardiac ion channel level, such as antiarrhythmics, have been in clinical use for several decades, well before the understanding that cardiac excitability was indeed a delicate equilibrium among the activity of specific ion channel classes and that the intimate mechanism of action of these congeners was outlined in detail. The recent progress in the molecular and functional characterization of cardiac ion channels has improved our understanding of their pathophysiological role in cardiac dysfunction, furthering the possibilities for the development of novel therapeutic strategies. These advancements, coupled with technical and conceptual improvements in drug-screening procedures, have had, and are likely to have in the future, a profound impact on drug discovery processes. The aim of the present chapter is to summarize the heterologous expression systems and the available screening techniques currently used in the characterization of the effects of specific modulators on cardiac ion channels, with particular emphasis on new technologies for high-throughput drug screening.