Increasing numbers of persons presenting for substance abuse treatment are multiple-substance users and their predominant drugs of choice are cocaine and alcohol. There are similarities in the treatment of alcohol and cocaine abuse, but important clinical differences need to be acknowledged. This chapter compares and contrasts the most recent epidemiology and clinical characteristics of both alcohol and cocaine abusers. First, use and abuse trends in the United States for both substances are described. The clinical characteristics of dependence on either substance are contrasted in detail, and finally, treatments are briefly described. Treatment for both disorders can be accomplished in the same setting if important demographic and pharmacological differences are addressed. In either disorder, comorbid psychopathology is frequent and appropriate treatment matching based on diagnosis is imperative.