Cellular impedance assays have been broadly utilized as a label-free approach for toxicity and drug discovery screening. The xCELLigence RTCA Cardio instrument sets itself apart from other impedance technologies by its rapid data acquisition rate (12.9 msec). This speed is fast enough to detect the contractile activity of beating cardiomyocytes, offering a relatively high throughput and robust strategy to noninvasively monitor the effects of test compounds on cardiomyocyte function. This chapter introduces the fundamentals and applications of cardiomyocyte impedance assays. A protocol detailing cardiomyocyte culture, data acquisition, and data analysis using the xCELLigence RTCA Cardio system is provided and considerations for assay design and data interpretation are discussed.