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The Magadi tilapia (Alcolapia grahami) is a cichlid fish that inhabits one of the Earth’s most extreme aquatic environments, with high pH (~10), salinity (~60 % of seawater), high temperatures (~40 °C), and fluctuating oxygen regimes. The Magadi tilapia evolved several unique behavioral, physiological, and anatomical adaptations, some of which are constituent and thus retained in freshwater conditions. We conducted a transcriptomic analysis on A. grahami to study the evolutionary basis of tolerance to multiple stressors. To identify the adaptive regulatory changes associated with stress responses, we massively sequenced gill transcriptomes (RNAseq) from wild and freshwater-acclimated specimens of A. grahami. As a control, corresponding transcriptome data from Oreochromis leucostictus, a closely related freshwater species, were generated. We found expression differences in a large number of genes …