Two-component systems are a highly conserved signal transduction pathway that enable bacteria to sense changes in their environment and adjust gene expression to adapt to nutrients, stresses, and other signals. The body of this work seeks to determine the extent to which E. coli uses these sensors as a network to process their environment. This is broken into two parts: (1) Whether cross talk can occur at the phosphorelay level and (2) whether the sensors are able to function as a combinatorial sensor. A combinatorial sensor is made up of a set of sensors, each of which is activated to different degrees by many inputs such that the pattern of their activation defines the signal. Using promoter reporters and flow cytometry, we measured the response of three two-component osmosensors in E. coli (envZ/ompR, cpxA/cpxR, and rcsC/rcsD/rcsB) to 38 chemicals including known inducers of the systems, membrane perturbing agents, alcohols and chemicals of industrial relevance. We found that each system responded to a wide spectrum of conditions and that the three systems are uncorrelated, meaning that unique patterns of gene expression are generated by even closely related chemical compounds. Of the eight possible patterns generated by a three sensor system, we observe five. This data show that bacteria are able to use a limited set of sensory components to identify a diverse set of compounds and environmental conditions.