Drug addiction is characterized by pathological motivation for drug-seeking and -use behaviors associated with the inability to inhibit such behaviors in spite of their clear adverse consequences (Kalivas and Volkow 2005). These features are clinically operationalized as a diagnosis of drug dependence based on an individual's fulfilling at least three of seven criteria defined by DSM-IV-TR (American Psychiatric Association 2000). The authors conform to the position (O'Brien et al. 2006) that drug addiction rather than dependence is more appropriate in referring to this maladaptive behavioral disorder and refer to drug dependence only when referring to clinical populations defined by DSM-IV-TR criteria. Drug addiction represents a major public health concern due to its high population prevalence, associated suffering and disability, and limited efficacy of extant therapies to promote recovery and relapse prevention. Understanding the underlying neurobiology of drug abuse and addiction offers the best promise to control drug addiction by identifying the bases of risk for addiction and targeting intervention strategies, uncoupling relapse from its precipitants, and minimizing the personal and social burden of addiction. This chapter represents a critical review of the current state of this understanding and a synthesis of knowledge into present and future directives for managing drug abuse and addiction. The treatment here of this topic is not meant to be comprehensive, but rather focuses on the authors' prioritization of those scientific areas of discovery that are perceived to be most relevant to curbing drug addiction. Attempts have been made to direct interested readers to more exhaustive treatments of less prioritized areas of addiction research findings.