Many clinical and epidemiologic studies have shown a high frequency of co-occurrence of substance abuse and psychiatric disorders, with important consequences from health and social perspective. However, the identification of reliable and valid diagnosis of psychiatric comorbidity in substance abusers is problematic, mainly because the acute or chronic effects of substance abuse can mimic symptoms of many other mental disorders, making difficult to differentiate psychiatric symptoms that represent effects of acute or chronic substance use or withdrawal, of those that represent an independent disorder. While DSM-IIII-R and earlier nomenclatures were unclear in differentiating independent from other psychiatric disorders, DSM-IV and DSM-IV-TR provided clearer guidelines in diagnosing psychiatric disorders in heavy users of alcohol and drugs, providing three categories: "primary" psychiatric disorders, "substance-induced" disorders, and "expected effects" of the substances, meaning expected intoxication and/or withdrawal symptoms that should not be diagnosed as symptoms of a psychiatric disorder. The use of the "Psychiatric Research Interview for Substance and Mental Disorders (PRISM)", a structured interview developed to improve the diagnosis of co morbidity in drug abusers according DSM-IV, supplies new opportunities in the clinical research in this field.