Halophilic microorganisms can thrive at hypersaline environments, and the mechanisms of salt-tolerance in halophilic microorganisms focused on the following three points: mechanisms of potassium-absorbing and sodium exclusion; accumulation of intracellular compatible solutes; the amino acid composition of halophilic enzyme. This paper reviewed the molecular mechanisms of salt-tolerance in halophilic bacteria and archaea, and discussed the prospects of the application in hypersaline wastewater treatment.