Biosynthetic toxic compounds from plants and cyanobacteria constitute a chemically diverse family of at least 20,000 compounds. Recent work with natural toxin databases and toxin characterization shows that the majority of natural toxins are polar and mobile, with toxicity ranging from low to very high, while persistence is highly variable. Natural toxins may be produced in high quantities—some exceeding 10 g/m2/year—resulting in high environmental loads. Recent phytotoxin monitoring indicates that one or more natural toxin is always present in a surface water sample, but that concentrations are highly variable often with pulses during rain events. Phytotoxins belong to many classes, but often with flavonoids and alkaloids dominating. Likewise, advanced monitoring discovers a wide spectrum of cyanobacterial metabolites that are released directly into surface waters during water blooms. Except of the few known cyanobacterial toxins, we have very limited info regarding their environmental fate and toxicity.The 16 papers in this article collection present examples of natural toxin occurrence, properties, fate and toxicity. The overarching conclusion is that natural toxins should be monitored and characterized regarding their risk potential, and that natural toxins of greatest expected risk should be evaluated as thoroughly as industrial xenobiotics. Cyanotoxins are well known water contaminants that should be removed for producing drinking water, while for phytotoxins the current knowledge base is very limited. We advocate to intensify research on natural toxins, and to address the evident knowledge gaps on natural toxin analysis/monitoring, physical–chemical properties and degradation/pathways, transport modelling, and toxicity. The complex and dynamic interplays between biotic and site conditions such as vegetation, toxic plant densities, climate, soil types, nutrients and radiation, play decisive roles for both biotoxin formation and fate. Environmental and toxicological research in biosynthesized compounds extends beyond natural toxins, with important perspectives for risk assessment of biopesticides, growth regulators and biomedicine (or biologicals collectively) produced by plants and microorganisms.