Benthic cyanobacteria are widespread in streams and rivers and have the potential to release toxins. In large numbers, these microorganisms and their toxins present a risk to human health. Cyanobacterial abundance in stream biofilms is typically related to single or a limited set of environmental factors, mainly light availability, water temperature, and nutrient concentrations. However, these factors may act synergistically with watershed characteristics and other stressors, such as anthropogenic pollutants, to affect cyanobacteria. We investigated the influence of multiple regional and local variables on the abundance of benthic cyanobacterial genera in streams using all subsets generalized additive modeling. We examined watershed factors (topography, geology, and climate) alongside in-stream factors (geomorphology, hydrology, pH, specific conductance, nutrients, organic contaminants, and dissolved metals) from 76 sites along an urban gradient in the northeast United States. Each genus responded to a distinct combination of environmental variables, demonstrating strong intergeneric variation in environmental selection of realized niches. Four of the 7 potentially toxigenic genera that we modeled were positively influenced by water temperature or nutrients. Nonetheless, watershed characteristics, streamflow, and/or other water quality pollutants were equally or more influential for the potentially toxigenic genera. Additionally, the relationships between cyanobacterial abundance and environmental factors varied in shape and direction across many genera. In particular, with increasing concentrations of herbicides, polychlorinated biphenyls, or metals, the abundance of roughly half of the affected genera decreased, while the others increased. These results likely demonstrate novel toxic effects of the pollutants on cyanobacterial genera in the environment, while indicating that unmeasured biotic interactions may lead to positive responses for other genera. Our results emphasize the need to consider variables beyond those that are most frequently measured or implicated (e.g., water temperature and nutrients) to more fully understand the environmental conditions that influence the distributions and abundance of potentially harmful cyanobacteria.