The development of drug-reinforced behavior is a transition process characterized by a relatively rapid shift from little or no drug-maintained responding to high, stable levels of responding. Animal studies of drug self-administration focus on how rapidly this process takes place or what percentage of animals acquire drug self-administration. It is essential to have animal models of acquisition because the process is difficult to study with drug-naive humans. Animal studies reveal a wide range of factors that can either accelerate or decrease acquisition of drug self-administration, such as environmental conditions (e.g., feeding conditions, palatable dietary substances, stress), pharmacological variables (e.g., drug dose, drug history, pretreatment drugs), and individual differences (e.g., reactivity level, age, sex, dietary preferences, genetics). This article discusses the methods used to study acquisition of drug-reinforced behavior in laboratory animals and the variables that have been reported to accelerate or prevent the acquisition of drug-reinforced behavior. An understanding of the conditions that can enhance acquisition in animals may help predict vulnerability to drug use in humans and lead to successful methods for prevention of drug abuse.