Phycotoxins, produced by cyanobacteria, dinoflagellates, and other algae, pose a significant threat to aquatic ecosystems and the aquaculture industry. Yet, many aquatic organisms—from invertebrates to fish—exhibit remarkable tolerance or resistance to these compounds. By integrating physiological, enzymatic, genetic, and epigenetic perspectives, this chapter provides a comprehensive overview of the mechanisms that allow invertebrates, fish, and even small mammals to tolerate, resist, or even thrive in the presence of these potent natural toxins. Along the way, we highlight how epigenetic regulation and the gut microbiome contribute to both immediate and transgenerational resilience, illustrating the dynamic interplay between organisms and their toxin-rich environment. Furthermore, we discuss the dual nature of cyanobacteria as both a toxin source and a nutrient reservoir, emphasizing the ecological and aquaculture relevance of these tolerance mechanisms. Finally, emerging tools, including artificial intelligence and dietary interventions, offer promising avenues to mitigate the effects of these toxins and harness the nutritional potential of toxin-producing algae. Altogether, understanding tolerance modes to phycotoxins provides critical insights into ecosystem resilience, aquaculture sustainability, and the evolutionary strategies that enable organisms to thrive in toxin-rich environments.