Air-breathing in vertebrates has evolved many times among the bony fish while in water. Its appearance has had a fundamental impact on the regulation of ventilation and acid-base status. We review the physico-chemical constraints imposed by water and air, place the extant air-breathing fish into this framework, and show how that the advantages of combining control of ventilation and acid-base status are only available to the most obligate of air-breathing fish, thus highlighting promising avenues for research.