Maintaining tight control over body fluid and acid/base homeostasis is essential for human health and is a major function of the kidney. This presentation will briefly outline new findings that have emerged over the past 2 or 3 years related to the function of two distinct cell types in the kidney collecting duct that are highly specialized to regulate water reabsorption (principal cells) and acid/base balance (intercalated cells) (1). Our work addresses the cell biological and signaling mechanisms that allow these cells to maintain systemic homeostasis by responding to physiological variations in plasma osmolality/volume and pH. Principal cells: The antidiuretic hormone vasopressin (VP) and its receptor, the V2R, play a central role in regulating the urinary concentrating mechanism by stimulating accumulation of aquaporin 2 (AQP2) water channels in the plasma membrane of collecting duct principal cells (1). This increases epithelial water permeability and allows osmotic water reabsorption to occur. Knowledge of the basic V2R signaling pathways and their effect on AQP2 trafficking in epithelial cells is critical for the development of new therapeutic strategies for diseases such as nephrogenic diabetes insipidus, in which VP signaling is defective. We will summarize efforts to bypass defective V2R signaling in principal cells to induce AQP2 plasma membrane accumulation with agents such as sildenafil citrate and statins, and with the hormone calcitonin. A novel chemical screening assay is currently being used to identify new compounds that may be useful to regulate AQP2 trafficking in the context of urinary concentrating disorders. Finally, the potential role of AQP2 in renal development via an interaction with integrins will be discussed (3). Intercalated cells: Urinary acidification due to the activation of intercalated cells is also critical to organ function, and defects lead to several pathological conditions in humans. We are striving to understand how these “professional” proton secreting cells respond to cellular and environmental cues, and some key work in this area was summarized in a recent review (2). One potential signaling pathway that intercalated cells might use to detect acid/base imbalances involves the soluble adenylyl cyclase, sAC, which could function as a luminal bicarbonate sensor in renal tubules to regulate acid/base homeostasis (6). By generating cAMP in response to elevated tubular bicarbonate, this pathway results in apical plasma membrane accumulation of the vacuolar H+ATPase (V-ATPase) (7), which increases acid secretion in an attempt to reduce systemic acidosis caused by inappropriate bicarbonate excretion. Other stimuli for proton secretion in these cells include, but are not limited to, aldosterone and angiotensin II. As part of this work, we generated mice that express EGFP in their intercalated cells, driven by the promoter of the B1 V-ATPase subunit (5), as well as mice that lack specific V-ATPase subunits. These animal models, as well as intercalated cells isolated from our EGFP-expressing mice by fluorescence activated cell sorting are being used for various studies, including proteomic (4) and gene expression analysis, cell specific signaling studies, kidney function analysis, and differentiation pathways. Some of this recent and ongoing work will be addressed in this presentation.