W. Horsley Gantt and Joseph V. Brady laid a rich foundation for understanding the concept of emotion, derived from 2 prominent traditions of physiology and psychology: classic conditioning and operant conditioning, respectively. This framework guided my fierce interest in motivation in general and the interaction between reward and stress, which began at John Hopkins with my thesis work under the guidance of Drs. Zoltan Annau, Solomon Synder, and Joseph Brady, among many others. Using the study of the neurobiology of addiction as a framework, I argue that drug addiction not only involves positive reinforcement associated with the rewarding effects of drugs of abuse but also involves another major source of reinforcement, specifically negative reinforcement driven by negative emotional states (termed the “dark side” of addiction). Excessive activation of the brain reward systems leads to antireward or a decrease in the function of normal reward-related neurocircuitry and persistent recruitment of the brain stress systems, both of which may be neurobiologically linked. Understanding the neuroplasticity of the neurocircuitry that comprises the negative reinforcement associated with addiction is a key to understanding negative emotional states in general and their pathophysiology.