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An expected outcome of climate change is intensification of the global water cycle, which magnifies surface water fluxes, and consequently alters salinity patterns. It is therefore important to understand the adaptations and limits of microalgae to survive changing salinities. To this end, we sequenced the 13.5 Mbp genome of the halotolerant green alga Picochlorum SENEW3 (SE3) that was isolated from a brackish water pond subject to large seasonal salinity fluctuations. Picochlorum SE3 encodes 7367 genes, making it one of the smallest and most gene dense eukaryotic genomes known. Comparison with the pico-prasinophyte Ostreococcus tauri, a species with a limited range of salt tolerance, reveals the enrichment of transporters putatively involved in the salt stress response in Picochlorum SE3. Analysis of cultures and the protein complement highlight the metabolic flexibility of Picochlorum SE3 that encodes genes involved in urea metabolism, acetate assimilation and fermentation, acetoin production and glucose uptake, many of which form functional gene clusters. Twenty-four cases of horizontal gene transfer from bacterial sources were found in Picochlorum SE3 with these genes involved in stress adaptation including osmolyte production and growth promotion. Our results identify Picochlorum SE3 as a model for understanding microalgal adaptation to stressful, fluctuating environments. [ABSTRACT FROM AUTHOR]