Because illicit drugs are now widely consumed, every doctor needs to know their acute medical consequences and complications. Here, we review the problems associated with the different drugs from a systems-based viewpoint. Apart from the respiratory depressant effect of opioids, crack cocaine is the most common cause of respiratory complications, mainly linked with its mode of use, with airway burns, pneumothorax, pneumomediastinum, and lung syndromes being well-recognised sequelae. Because of its marked cardiovascular effects, cocaine is also a major cause of coronary syndromes and myocardial infarction. Amphetamines may produce similar effects less commonly. Hyperthermia may occur with cocaine toxicity or with 3,4-methylenedioxymethamphetamine (MDMA) due to exertion or from serotonin syndrome. Cerebral haemorrhage may result from the use of amphetamines or cocaine. Hallucinations may follow consumption of LSD, amphetamines, or cocaine. MDMA is a major cause of acute severe hyponatraemia and also has been linked with hepatic syndromes. Collapse, convulsions, or coma may be caused in different circumstances by opioids, MDMA, or gamma hydroxybutyrate and may be aggravated by other sedatives, especially alcohol and benzodiazepines. Recognition of these acute complications is urgent, and treatment must be based on an understanding of the likely underlying problem as well as on basic principles of supportive care.