Fluctuating salinity is symptomatic of climate change challenging aquatic species. The melting of polar ice, rising sea levels, coastal surface and groundwater salinization, and increased evaporation in arid habitats alter salinity world-wide. Moreover, the frequency and intensity of extreme weather events such as rainstorms and floods increase, causing rapid shifts in brackish and coastal habitat salinity. Such salinity alterations disrupt homeostasis, and ultimately diminish fitness, of aquatic organisms by interfering with metabolism, reproduction, immunity, and other critical aspects of physiology. Proteins are central for these physiological mechanisms. They represent the molecular building blocks of phenotypes that govern organismal responses to environmental challenges. Environmental cues regulate proteins in concerted fashion, necessitating holistic analyses of proteomes for comprehending salinity stress responses. Proteomics approaches reveal molecular causes of population declines and enable holistic bioindication geared towards timely interventions to prevent local extinctions. Proteomics analyses of salinity effects on aquatic organisms have been performed since the mid-1990s, propelled by the invention of two-dimensional protein gels, soft ionization techniques for mass spectrometry, and nano-liquid chromatography in the 1970s and 1980s. This review summarizes the current knowledge on salinity regulation of proteomes from aquatic organisms, including key methodological advances over the past decades.