Acid-base balance is one of the most tightly regulated physiological processes. Accumulation of metabolic CO2 produced at the tissues causes extra- or intracellular acidosis that can disrupt cellular processes. Consequently, fish have a well-developed system for CO2 transport and excretion; however, the system varies significantly among fish groups, which we review in this chapter. Elevated environmental CO2 that occurs naturally or due to anthropogenic factors (e.g., climate change and in aquaculture), in both freshwater and seawater, induces a rapid acid-base disturbance in fish. The resulting acidosis is compensated by a net elevation in plasma HCO3 − in exchange for [Cl−], primarily through processes at the gills, but also the kidney. The rate and completeness of acid-base compensation during CO2 exposure is affected by water ion composition, and at high CO2 levels, there appears to be an upper limit to the increase in plasma HCO3 −. Fish that naturally live in such high CO2 environments appear to have an exceptional capacity for intracellular pH regulation. While it has long been thought that fish would not be affected by climate change relevant CO2 levels, negative physiological effects are seen. The effect of fluctuating CO2 levels in both marine and freshwater environments may be especially problematic, and an area where more research is required.