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The use of 3-D multicellular spheroid (MCS) models is increasingly being accepted as a viable means to study cell-cell, cell-matrix and cell-drug interactions. Behavioral differences between traditional monolayer (2-D) cell cultures and more recent 3-D MCS confirm that 3-D MCS more closely model the in vivo environment. However, analyzing the effect of pharmaceutical agents on both monolayer cultures and MCS is very time intensive. This paper reviews the use of electrical impedance spectroscopy (EIS), a label-free whole cell assay technique, as a tool for automated screening of cell drug interactions in MCS models for biologically/physiologically relevant events over long periods of time. EIS calculates the impedance of a sample by applying an AC current through a range of frequencies and measuring the resulting voltage. This review will introduce techniques used in impedance-based analysis of 2-D systems; highlight recently developed impedance-based techniques for analyzing 3-D cell cultures; and discuss applications of 3-D culture impedance monitoring systems.