Ketamine was introduced as an anaesthetic in the 1960s and continues to be used therapeutically both as an anaesthetic and also increasingly in pain management. In addition to use in humans, ketamine is widely used as an anaesthetic in veterinary medicine. It is used in research as a pharmacological model of schizophrenia. In recent years, ketamine has increasingly been used as a recreational drug. Though it is now a controlled substance in many countries in the world due to its psychotropic properties, its use as a recreational drug has become a worldwide phenomenon. In addition to the risk of acute toxicity associated with ketamine use, long-term ketamine toxicity can produce significant adverse effects and consequently lead to a burden on healthcare resources. In this chapter, we summarize the pathological changes in the different organs of animal models and humans, including its toxicity on central nervous system (CNS), urogenital system, intestine, pancreas, adrenal gland, liver, heart and immune system. The effects on the combination of ketamine and alcohol were also addressed in a number of the models of chronic ketamine toxicity. This is followed by a summary of the human data on patterns of acute and chronic toxicity reported from recreational and dependent use of ketamine.