Systems biology analyses of metabolomics and transcriptomics data from various SLC 22 transporter knockouts suggests a broad role in metabolism. Furthermore, classical signaling molecules (eg. prostaglandins, cyclic nucleotides, odorants and steroid conjugates) are among the best ligands for several original and more recently identified SLC22 family members. This, together with interesting tissue expression patterns in barrier epithelia under normal and perturbed conditions, as well as during organ development, has led to the hypothesis that these and other so-called drug transporters function as part of a “Remote Sensing and Signaling System” critical in the maintenance of local and systemic concentrations of rate-limiting metabolites and signaling molecules. This Remote Sensing and Signaling System involving SLC and ABC “drug” transporters may be important for inter-organ remote communication, functioning in parallel with other regulatory systems (eg. endocrine, growth factor, autonomic) as well communication between organisms (eg. gut microbiome-human).