Oestrogen-related receptor a (ERRa) is an orphan nuclear receptor which is important for adaptive metabolic responses under conditions of increased energy demand, such as cold, exercise and fasting. Importantly, metabolism under these conditions is usually accompanied by elevated production of organic acids, which may threaten the body acid-base status. Although ERRa is known to help regulate ion transport by the renal epithelia, its role in the transport of acid-base equivalents remains unknown. Here, we tested the hypothesis that ERRa is involved in acid-base regulation mechanisms by using zebrafish as the model to examine the effects of ERRa on transepithelial H þ secretion. ERRa is abundantly expressed in H þ -pump-rich cells (HR cells), a group of ionocytes responsible for H þ secretion in the skin of developing embryos, and its expression is stimulated by acidic (pH 4) environments. Knockdown of ERRa impairs both basal and low pH-induced H þ secretion in the yolk-sac skin, which is accompanied by decreased expression of H þ -secreting-related transporters. The effect of ERRa on H þ secretion is achieved through regulating both the total number of HR cells and the function of individual HR cells. These results demonstrate, for the first time, that ERRa is required for transepithelial H þ secretion for systemic acid-base homeostasis.