Our research addresses questions on fundamental biological processes across scales, from molecules to cells to tissues. Our predominant focus is determining how protein functions and cell processes are regulated by intracellular pH (pHi) dynamics, specifically for cell migration, epithelial plasticity and cancer cell behaviors. Cancer cells have a higher pHi than non-transformed cells, which as we describe (Nat Rev Cancer 2011, 11:671; J Cell Sci 2017, 130:663) enables tumorigenic behaviors and metastatic progression. However, we have limited understanding of how this occurs at the molecular level and can be exploited to limit disease progression. In collaboration with Matthew Jacobson (computational biology) at UCSF we are bridging structural and cell biology to determine the design principles of pH sensors, defined as proteins with activities or ligand-binding affinities that are regulated by cellular pH dynamics. As we describe (Ann Rev Biophys 2013, 42:289), we view the design of pH sensors to include protonation as a post-translational protein modification, analogous to phosphorylation and acetylation. In contrast to other post-translational modifications, however, protonation cannot be detected by mass spectrometry or antibodies and is not catalyzed by an enzyme, which makes investigating pH sensors more challenging. I will discuss our work on the design and function of pH sensors regulating cell polarity, actin filament assembly and focal adhesion remodeling, as well as recent findings revealing how increased pHi is necessary for oncogene-induced dysplasia and sufficient for dysplasia in the absence of oncogenes (eLife 2015, 4:e03270). I will also present unpublished work on beta-catenin as a previously unrecognized pH sensor with decreased stability at pHi > 7.4, as well as gain of pH sensing by recurring somatic arginine > histidine mutations in cancers, which enables tumorigenic behaviors at the higher pHi of cancers. Finally, I will present new (J Cell Biol 2016, 215:345) and ongoing work on pHi-dependent mouse and Drosophila stem cell differentiation, which highlights evolutionary conservation of pHi-dependent cell behaviors.