Ion homeostasis in cyanobacteria is a complex and finely tuned process that involves the functions of a variety of protein transporters and regulatory mechanisms. These ensure cyanobacterial cells can maintain stable intracellular conditions in diverse, fluctuating, and often extreme environments. Ion homeostasis also supports key physiological functions, such as photosynthesis and nitrogen fixation and stress responses. In halotolerant cyanobacteria, substantial evidence has shown that Na+/H+ antiporters and ATPase-driven pumps (Na+-ATPase) play crucial roles in maintaining ion homeostasis, particularly in high-salt environments. Recent research and advances in genomics, transcriptomics, and proteomics tools have led to the identification of novel Na+/H+ antiporter genes in halotolerant cyanobacteria. A large repertoire of Na+/H+ antiporter and Na+-ATPase genes have been found to be essential for the complex molecular system present in halotolerant cyanobacteria. Functional characterization of these protein transporters contributes to understanding their molecular mechanisms, structure–function relationships, physiological aspects, and halotolerance adaptations.