Whole lake monitoring of hypertrophic Lake Taihu, China, was conducted during the summers of 2009-2010, with the intent of identifying environmental factors influencing Microcystis bloom formation and promoting the growth of toxigenic strains (mcyE possessing). Low N:P ratios (replete N & P)appeared to select for toxigenic populations of Microcystis spp., whereas nontoxic Microcystis spp. strains were dominant in more nutrient limited regions of the lake. Chlorophyll a (Adj. R(2) = 0.83, p < 0.0001) was equally predicative of microcystin variance across the lake as fluorescence based real-time quantitative PCR (qPCR) measurements of microcystin synthetase E (mcyE) gene equivalents (Adj. R(2) = 0.85, p < 0.0001). Interestingly, chlorophyll a was identified as a more robust and useful metric for predicting microcystin concentrations than qPCR measurements enumerating the total Microcystis population based on c-phycocyanin (α subunit; cpcA) gene equivalents (Adj. R(2) = 0.61, p < 0.0001). Overall, the lakewide composition of Microcystis spp. was highly variable over time and space, and on average the population consisted of 36 ± 12% potentially toxic cells. On the basis of this study's findings, a framework for the design and implementation of a water safety plan for Taihu water quality managers and public health officials is proposed.