Cation and protons perform a substantial role in all the organism and its homeostasis within the cells are maintained by the cation-proton antiporters (CPAs). CPA is the huge family of the membrane transporter protein throughout the plant and animal kingdom including microorganism. In human, any malfunctioning of these proteins may lead to severe diseases like hypertension, heart diseases etc and CPAs are recently proposed to be responsible for the virulent property of various pathogens including Vibrio cholerae, Yersinia pestis etc. Human Sodium-Proton exchangers (Na+/H+ exchangers, NHEs) are crucial in ion homeostasis whereas Ec-NhaA, Na + -H + Antiporters maintain a balance of Na+ and proton in E. coli, regulating pH and cell volume within the cell. These Sodium-Proton antiporters are found to be responsible for the virulence in various pathogens causing human diseases. Understanding of these CPAs may assist investigators to target such human diseases, that further may lead to establishing the effective path for therapeutics or drug designing against associated human disease. Here we have compiled all such information on CPAs and provide a systematic approach to unravel the mechanism and role of antiporter proteins in a wide range of organisms. Being involved throughout all the species, this review on cation-proton antiporters may attract the attention of many investigators and concerned researchers and will be provided with the recent detailed information on the role of CPA in human health. Copyright © 2021 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.