Cyanobacteria-dominated blooms in Upper Klamath Lake, Oregon, create poor water quality and produce microcystins that may be detrimental to local wildlife and human health. Genetic tools, including high-throughput DNA sequencing and quantitative polymerase chain reaction (qPCR), have been shown to improve the identification and quantification of key groups associated with these blooms over more traditional techniques. We examined the seasonal and interannual variations in nutrient (nitrogen and phosphorus) concentrations between 2013 and 2014 to describe the relations between these factors and the growth dynamics of Aphanizomenon and toxigenic Microcystis as described by DNA sequencing and qPCR. Although total nutrients and chlorophyll a concentrations were similar between years, qPCR results showed the cyanobacterial populations to be 40 times larger in 2014 and indicated a large shift from an Aphanizomenon-dominant, low microcystin-level regime in 2013 to one dominated later in the season by microcystin-producing Microcystis in 2014. In both years, the transition from Aphanizomenon to Microcystis was coincident with a late-season increase in nitrite-plus-nitrate concentrations and in dissolved inorganic nitrogen to dissolved inorganic phosphorus (DIN:DIP) ratios. However, these increases did not explain the large interannual differences in total cyanobacteria abundance. Rather, we hypothesized that year-to-year differences in bioavailable phosphorus, which also manifested as lower total nitrogen to total phosphorus (TN:TP) ratios, were responsible.