Mushroom consumption is a global tradition that is still gaining popularity. However, foraging for wild mushrooms and accidental ingestion of toxic mushrooms can result in serious illness and even death. The early diagnosis and treatment of mushroom poisoning are quite difficult, as the symptoms are similar to those caused by common diseases. Chemically, mushroom poisoning is related to very powerful toxins, suggesting that the isolation and identification of toxins have great research value, especially in determining the lethal components of toxic mushrooms. In contrast, most of these toxins have remarkable physiological properties that could promote advances in chemistry, biochemistry, physiology, and pharmacology. Although more than 100 toxins have been elucidated, there are a number of lethal mushrooms that have not been fully investigated. This review provides information on the chemistry (including chemical structures, total synthesis, and biosynthesis) and the toxicology of these toxins, hoping to inspire further research in this area.