This chapter describes how substance use, substance-related problems, and substance use disorders (SUDs) have been viewed over time and in different cultures. Substance problems and inebriety were historically understood through a moralistic perspective, although the description of substance problem syndromes as medical diseases or disorders has a long history. Systematic attempts to develop and refine diagnostic criteria for SUDs began in the middle of the twentieth century and continue to this day. Research has identified limitations of existing diagnostic criteria for SUDs, which can aid the development of future classification systems. Culture plays a role in how substance use and SUDs are conceptualized and in how symptoms are manifested and interpreted. Modern theory of the nature of substance dependence emphasizes how chronic substance use can produce neuroadaptations in brain systems involved in reward, motivation, affective regulation, inhibitory control, and tolerance/withdrawal, all of which can contribute to compulsive substance use behavior.