Cell-based assays have become a favored format for drug discovery because living cells have relevant biological complexity and can be highly multiplexed to screen for drugs and their mechanisms. In response to a changing extracellular environment, disease and/or drug exposure, cells remodel bioenergetic pathways in a matter of minutes to drive phenotypic changes associated with these perturbations. By measuring the extracellular flux (XF), that is the changes in oxygen and proton concentrations in the media surrounding cells, one can simultaneously determine their relative state of aerobic and glycolytic metabolism, respectively. In addition, XF is time-resolved and non-invasive, making it an attractive format for studying drug effects in vitro.