Salinity is a critical abiotic stress, which significantly impacts the agricultural yield worldwide. Identification of the molecular mechanisms underlying the salt tolerance in euhalophyte Suaeda salsa is conducive to the development of salt-resistant crops. In the present study, high-throughput RNA sequencing was performed after S. salsa leaves were exposed to 300 mM NaCl for 7 days, and 7,753 unigenes were identified as differently expressed genes (DEGs) in S. salsa, including 3,638 increased and 4,115 decreased unigenes. Moreover, hundreds of pathways were predicted to participate in salt stress response in S. salsa by Gene Ontology (GO), MapMan and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, including ion transport and sequestration as well as photoprotection of photosystem (PS) II. The GO enrichment analysis indicated that genes related to ion transport, reactive oxygen species (ROS) scavenging and transcriptional factors were highly expressed upon NaCl treatment. The excessive Na + and cl − ions were supposed to be absorbed into the vacuole for ion sequestration and balance adjustment by potassium transporters (such as KEA3) with high expressions. Moreover, we predicted that mutiple candidate genes associated with photosynthesis (such as PSB33 and ABA4), ROS (such as TAU9 and PHI8) and transcriptional regulation (HB-7 and MYB78) pathways could mitigate salt stress-caused damage in S. salsa. Salt stress, one of the most important abiotic factors, greatly affects global agricultural productivity. It is estimated that about 6.0% of the land worldwide, more than 800 million ha, is either salt affected or has been subjected to soil salinization 1,2. The food production is increased at a rate of 1.8% per year, the world population is expected to exceed 9.5 billion people by 2050 (http://www.fao.org/wsfs/world-summit/en), and 30% of the cultivable soils will become unusable due to salt stress, all of which pose serious challenges to salt alleviating technologies for agricultural research 3. Plants can be divided into halophytes and glycophytes according to the ability of salt tolerance. External salt concentration of 86 mM NaCl has been taken as a general limit, above which the plant yield of glycophytes is severely reduced 4,5. Nevertheless, halophytes can grow in a surrounding containing even 200 mM NaCl or more, and they are further categorized into euhalophytes, recretohalophytes and pseudo-halophytes 6-9. Salt-diluting halophytes, such as sea beet and other succulent halophytes, are able to balance low external water potential and generate turgor by accumulating high contents of internal Na + and Cl − ions in their vegetative tissues 10-12. Recretohalophytes are typical halophytes, which have developed a series of adaptive secretory structures, including salt glands and salt bladders, for salt excretion 2,4,5,13-15. These characteristic visible structures of recretohalophytes play a crucial role in excreting excess salt out of the plants to avoid ionic damage 13,14,16-20. Euhalophytes ...