Bacteria employ signaling proteins like bacterial histidine kinases (HKs) to sense environmental stimuli and initiate a transcriptional response through a series of conformational changes and enzymatic steps. Despite the prevalence of these receptors, we still lack significant understanding of how specific signals are detected and propagated through the protein scaffold to induce switch-like behavior with finely tuned specificity, sensitivity, and transcriptional output. Generating large-scale HK genotype-phenotype relationships will enable us to parse out allosteric networks that enable and regulate intramolecular signal transduction, providing molecular insights into the complex mechanisms by which these organisms sense and adapt to their environment.