Cation fluxes are known to drive cellular signaling events, whereas anions, in large part, are considered to function as counterions to neutralize these changes. But could anions be dynamic cellular signals just like cations? This paradigm shifting question, in large part, has been overlooked from the chemical biology perspective, despite the fact that anion dysregulation is implicated in a variety of diseases including cystic fibrosis, chronic pain, autism, and cancer. By creating and applying a new toolkit for anions, we can start to answer this question. Currently, we are developing small molecule, macromolecular, and genetically encoded biosensors to build a molecular level picture of picture into the how, when, where, and why of what anions are actually doing in living systems. With these tools, we aim to not only define the molecular criteria required for aqueous anion detection but will also make fundamental contributions to understanding the roles of anions in cellular signaling. Most recently, we have started to create biocompatible materials that can be used for the diagnosis and treatment of anion dependent-diseases along with exploring ‘omics’ approaches to uncover the roles that anions could play in cellular signaling. We are grateful for research support from the Welch Foundation and the National Institute of General Medical Sciences.