Multiple drug abuse may involve the whole range of abused drugs, but the most critical problems exist with cocaine, alcohol, opioids, and benzodiazepines. The medical and psychosocial consequences of abusing these drugs in various combinations are often more severe than abusing each drug alone, and specific combinations of treatment options may be needed for many of these drugs. These combination treatments may include relapse prevention psychotherapies targeted toward drug-related cues that are specific to each type of drug as well as pharmacotherapies targeted toward specific drugs of abuse, such as naltrexone for opioid abuse and disulfiram for alcohol abuse. Few controlled clinical trials are available with multiple drug abusers, but successful treatments using pharmacological adjuncts such as disulfiram and amantadine have been described with cocaine-abusing or alcoholic methadone-maintained patients.