The dependence syndrome concept has been defined by both behavioral and biological changes that occur with excessive substance use. Originally developed for alcohol, this concept was adopted for diagnosing dependence on other substances of abuse, although little research had been done to test its validity for other drugs. This chapter addresses the validity of the dependence concept across drug classes in the following ways. First, we compare the dependence items for three different drugs, alcohol, opiates, and cocaine, in measures of internal consistency. Second, biological items are correlated with behavioral items to assess the usefulness of defining dependence by both biological and behavioral criteria. Finally, we draw upon ideas developed in motivational theory and apply these to the dependence syndrome concept. These analyses, while supporting the validity of the concept, lead to suggestions for refining the concept of dependence.