Thermal stress, encountered frequently in aquaculture, affects diverse physiological processes and behavior of fish; however, the mechanism underlying these effects may vary among species. Half-smooth tongue sole (Cynoglossus semilaevis) widely inhabits Asian coastal waters and has been intensively cultured in China. In this study, the transcriptomes of three tissues (gill, liver and muscle) of half-smooth tongue sole stressed at temperatures up to 35°C were profiled and compared with those of the fish living at a normal temperature of 25°C. Of 105,228 transcripts, 23,213 were annotated in GO terms, and 718, 1236 and 561 were found to express differentially in gill, liver and muscle from control, respectively. Of the differentially expressed genes, 119 were shared by all three tissues. Tissue-overlapping transcripts and the pathways and functions they defined may underline the primary response of fish to thermostressing. High temperature may cause directly protein mis-folding and hypoxia. Cells suffering thermostress either survive hypoxia or are eliminated by immune system. High temperature may have interacted indirectly through HSPs with HIF-1 and JAKs/STATs signaling pathways. The former up-regulates the expression of hypoxia inducible genes while the later up-regulates the expression of genes associating with insulin and NOD-like receptors signaling pathways. Insulin pathway functions to sustain homeostasis of sugar and lipids, aiding to survive cells, while NOD-like receptors signaling pathway strengthens immune, apoptotic and inflammatory responses, helping to survive cells. These understandings may help improve our culturing practice, the culture performance of half-smooth tongue sole and its breeding.