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. To build a molecular level picture of picture into the how, when, where, and why of what anions are actually doing in living systems, we are developing small molecule and genetically encoded biosensors. In parallel, efforts are currently underway to create biocompatible materials that can be used for the diagnosis and treatment of anion dependent-diseases, along with exploring bioinformatics/transcriptomics approaches to discover new anion-binding proteins and roles that anions could play in cellular signaling. 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. We are grateful for current and past research support from the University of Texas System STARs program, Welch Foundation, and National Institute of General Medical Sciences.