Global climate change has led to a marked increase in both the frequency and severity of harmful cyanobacterial blooms, threatening the quality of drinking water resources, safety of recreational opportunities, as well as the viability of aquatic ecosystems. In this study, a wide-ranging literature review was performed, followed by an analysis to elucidate the primary factors mediating cyanotoxin threats and strategies to best mitigate human and ecosystem health impacts. The study examines the distribution and intensity of major cyanotoxins resulting from harmful bloom events, with a focus on the United States. It discusses governmental efforts to manage and monitor blooms across the continental United States. The fate and persistence of cyanotoxins are examined through compilation and analysis of various experimentally determined physicochemical metrics such as biodegradation and photodegradation half-lives, bioaccumulation factors, and sediment partition coefficients. These metrics provide a quantitative means to assess how cyanotoxins are distributed (i.e., in organisms, suspended particulate, or sediments) and ultimately removed from the environment through natural biological (i.e., bacterial degradation) or physicochemical mechanisms (i.e., photolysis, oxidation). The analysis reveals that the current predictive understanding of cyanotoxin biodegradation, a primary factor influencing persistence in the environment, is quite limited. Reliable cyanotoxin biodegradation models capable of reproducing the degradative kinetics and efficiencies observed in the field, accounting for variable environmental conditions (temperature, pH, presence of dissolved organic matter), and coupling physicochemical fate and distribution mechanisms are required to properly inform and to safeguard human and ecosystem health. In addition, existing regulations governing cyanotoxin concentrations in water solely focus on water ingestion as the means of exposure, neglecting other routes and health endpoints in exposure to contaminated water bodies. This study underscores the importance of investigating cyanotoxin biodegradation in natural settings, developing integrated cyanotoxin environmental fate and transport modeling frameworks, and advancing novel recreational human end ecosystem health risk assessments as critical areas for future research. Through integration of innovative cyanotoxin fate prediction and human/ecological health risk assessment frameworks, an improved understanding of cyanobacterial bloom management and mitigation can be achieved, focusing on programs and strategies that are preventative, rather than reactive, in concept and application. Ultimately, this review highlights that developing and implementing such preventative programs will be requiring highly localized efforts, as significant variation in cyanotoxin types and concentrations, environmental fate, and persistence metrics, and resulting human/ecological impacts have been reported in previous studies. Therefore, integrated frameworks for detection, monitoring, and prediction of future cyanobacterial bloom events must be flexible, yet granular enough to reliably inform preventative management and mitigation scenarios across a variety of spatiotemporal scales.