Not the mere procurement and use of drugs, but the fact that patterns of seeking and taking become compulsive after prolonged drug use is a defining characteristic of drug addiction. Development of a therapy that targets the compulsive aspects of drug use and thus addresses addiction at its core would therefore be very desirable. In the present review, we will discuss animal studies that attempt to model loss of control over drug use. Furthermore, we will try to put these studies in a theoretical perspective, and discuss the hypothesized underlying neural and behavioral mechanisms.