Harmful cyanobacterial blooms (CyanoHABs) can entail tremendous ecological and economic loss, and they are still expanding globally. However, the mechanisms of CyanoHABs remain complicated and confusing. This study is an attempt to establish a comprehensive mechanism of harmful cyanobacterial blooms through the following aspects: evolutionary radiation, nutrient requirements, functional genomic repertoires, symbioses with other species, and genome-scale metabolic networks. Through the evolutionary and ecological lenses, we underscored that the formation of CyanoHABs is an inevitable consequence when low nutrient requirement meets water eutrophication. To unravel the functional genomic repertoire of cyanobacteria, we not only retrieved all the available genome sequences of Microsystis aeruginosa, a dominant bloom species of freshwater cyanobacteria, but also sequenced the microbiome including cyanobacteria and their associated bacteria in Taihu freshwater samples. A stable metabolic core under various growth conditions was shared by all geographical Microsystis aeruginosa strains. More importantly, cyanobacteria possess a superior functional repertoire without many prior local adaptations. Another notable feature of cyanobacteria is their capability to form a symbiosis with other organisms. We, therefore, investigated the organizing principles for microbiome assembly in Taihu using a combination of molecular biology, biophysics, and bioinformatics techniques. We found that partners of symbiotic organisms had a metabolic dependency, and the combined metabolic network showed expanded metabolic capabilities than the network alone for each partner. Overall, the formation of CyanoHABs is a result of the interactions between the environment and the functional genomic repertoire of cyanobacteria.