Picocyanobacteria (mainly Synechococcus and Prochlorococcus) contribute significantly to oceanic primary production. Unlike Prochlorococcus, which is mainly constrained to the warm and oligotrophic ocean, Synechococcus has a ubiquitous distribution. Synechococcus is present in freshwater, estuarine, coastal, and open ocean habitats. They have also been found in polar regions and hot springs. Endemic to the hot and the cold, the saline and the fresh, and every condition in between, Synechococcus appears to have the capability to adapt and tolerate nearly any environment and climate. This ability to adapt to any aquatic environment is possible through their genome plasticity, a character that is not present in the Prochlorococcus.Due to the differential distribution of the genera, Synechococcus is considered a generalist and Prochlorococcus is considered a specialist in ecological theory. More than 400 picocyanobacterial genomes have now been sequenced, and this large genomic resource enables comprehensive genome mining and comparison. One possibility is to study the prevalence of Toxin-Antitoxin (TA) systems in picocyanobacterial genomes. TA systems are present in nearly all bacteria and archaea and are involved in cell growth regulation in response to environmental stresses. However, little is known about the presence and complexity of TA systems in picocyanobacteria. By querying 77 complete genomes of freshwater, estuarine, coastal and ocean picocyanobacteria, Type II TA systems (the most well studied TA family) were predicted in 27 of 33 (81%) Synechococcus strains, but no type II TA genes were predicted in any of the 38 Prochlorococcus strains. The number of TA pairs varies from 0 to 80 in Synechococcus strains, with a trend for more type II TA systems being predicted in larger genomes. A linear correlation between the genome size and the number of putative TA systems in both coastal and freshwater Synechococcus was established. In general, open ocean Synechococcus contain no or few TA systems, while coastal and freshwater Synechococcus contain more TA systems. The type II TA systems inhibit microbial translation via ribonucleases and allow cells to enter the “dormant” stage in adverse environments. Inheritance of more TA genes in freshwater and coastal Synechococcus could confer a recoverable persister state which would be an important mechanism to survive in variable environments. Different genotypes of Synechococcus are present in the Chesapeake Bay in winter and summer. Winter isolates of Synechococcus have shown high tolerance to cold conditions and other stressors. To explore their potential genetic capability, complete genomes of five representative winter Synechococcus strains CBW1002, CBW1004, CBW1006, CBW1107, and CBW1108 were fully sequenced. These five winter strains share many homologs that are unique to them and not shared with pelagic Synechococcus. Winter Synechococcus genomes are enriched with particular desaturases, chaperones, and transposases. Similar amino acid sequences and annotated features were not found in distantly related Synechococcus from Subcluster 5.1. These shared genomic features between the winter strains imply that maintaining membrane fluidity, protein stability, and genomic plasticity are important to cold adaption of Synechococcus. The winter strains also contain genes that are not traditionally considered with the canonical bacterial cold shock response. They contain a particularly high abundance of Type II TA pairs with complex association networks. They feature promiscuous toxins, like VapC, that pair with multiple antitoxins, which support the mix and match hypothesis. Winter strains also contain more monogamous toxins, such as BrnT, which tend to pair with their traditionally named antitoxin, BrnA. Expression of certain TA transcripts in response to environmental stress has been observed in the model strain CB0101, and the activity of one TA pair in CB0101 for growth arrest has been experimentally confirmed via heterologous expression in E. coli. My thesis work has identified interesting genetic systems related to niche partitioning of picocyanobacteria, particularly among the Chesapeake Bay Synechococcus. Future studies are paramount to understand the functional role of TA systems, desaturases, chaperons, and transposases of picocyanobacteria under various environmental stressors.