Activation of endogenous receptors (GPCR, tyrosine kinase and nuclear receptors) results in changes in the cytoskeleton and related morphological changes in cells. Changes in electrical impedance associated with these morphological changes in the presence of agonists and antagonists of these receptors can be used to evaluate hits from HTS assays. In this chapter, the basics of impedance assays and the use of two instruments available for these applications are discussed. Examples of GPCR activation and a sample protocol are also provided for the benefit of beginners and experienced investigators.