The indigenous neurotoxic red tide dinoflagellate, Karenia brevis, is a constant threat to manatee (Trichechus manatus latirostris) survival, particularly in southwest Florida. Since 1996, more than 500 manatee deaths and 33 manatee rescues have been attributed to red tide. Sporadic cases of brevetoxicosis can be diagnosed any time of the year; however, when a bloom coincides with manatee migration from warm-water sites, mass mortality may occur. Also, long after or remote from a bloom, ingestion of seagrass with accumulated brevetoxins can lead to mass mortality. Today, no feasible management actions exist to mitigate manatee exposure to red tide. Manatees with acute brevetoxicosis demonstrate neurologic symptoms, including tremors, seizures, paresis, and paralysis. Emergency response is critical to prevent affected manatees from drowning, and once rescued, most animals are successfully rehabilitated. However, the majority of manatees with brevetoxicosis are found dead. Pathologic findings are non-specific and include congestion of airways and meninges, as well as copious amounts of blood on sections of liver, kidneys, and lungs. Since 2002, the quantification of brevetoxins using a competitive enzyme-linked immunosorbent assay has greatly enhanced diagnosis. Diagnosis is based on gross findings, brevetoxin concentrations in tissues and ingesta and in environmental samples such as water, sediment, and seagrass. However, despite advances in the diagnosis of acute brevetoxicosis, little is really known about mechanisms of brevetoxin pathophysiology in manatees and chronic effects on health. Continuing research on samples from manatees exposed to brevetoxins, including carcasses and rescued manatees, is important to better understand the epidemiology and pathogenesis of this significant cause of manatee mortality.