Label-free technologies based on electrical impedance or refractive index are new tools for measuring a cell-based functional response. Although the technologies are relatively new to high throughput screening cell-based applications, they are rapidly generating interest in that they are able to measure a phenotypic response using cells natively expressing the target protein without using dyes or cellular extracts. In addition, one can measure the cellular response using a kinetic mode resulting in an assay potentially rich in content. This article will describe these technologies and their applications in measuring cell proliferation, cell attachment and spreading, cell apoptosis and their application for several receptor target classes, including receptor tyrosine kinases and G protein-coupled receptors. The potential utility and drawbacks of these tools for high throughput screening, directed screening and compound profiling will also be discussed.