This dissertation investigates how the settings of drug use influence the affective and neurobiological response to heroin versus cocaine in addicts. Chapter 1 reviews the neuropharmacology of heroin and cocaine and the theoretical background for drugs-settings interactions, including a detailed discussion of findings from previous studies in animals and humans that show how the same settings can influence in opposite directions the reinforcing effect of heroin and cocaine. Cocaine self-administration, for example, was greatly facilitated when rats were tested outside the home environment relative to rats test at home. The opposite pattern was found for heroin. Translational studies in humans yielded similar results. Indeed, heroin and cocaine co-abusers reported using the two drugs in distinct settings: heroin preferentially at home and cocaine preferentially outside the home. The aim of this dissertation is to determine whether the setting could also influence in opposite manner the affective and neurobiological response to heroin and cocaine in human addicts. Chapter 2 illustrates the findings of a study aimed at testing the hypothesis that the affective state experienced under cocaine or heroin is the result of an interaction between central and peripheral drug effects and the surroundings of drug use. According to this hypothesis, when cocaine is taken at home there is a mismatch between the familiar environment and the peripheral effects such as arousal, increased heart rate, increased respiratory rate, and increased muscular tension (which are usually produced in stressful situations). This mismatch dampens cocaine-rewarding effects. A mismatch would also occurs when heroin (which produces sedation and decreases heart rate, respiratory rate, and muscular tension) is used outside the home in contexts requiring vigilance. We found indeed that co-abusers subjectively experienced opposite changes in arousal, heart rate, respiratory rate, and muscular tension in response to cocaine (increase) versus heroin (decrease). Most important, using a novel two-dimensional visual test, we found that in agreement with the working hypothesis the valence of the affective state produced by heroin and cocaine shifted in opposite directions as a function of the setting of drug use: heroin was reported to be more pleasant at home than outside the home, and vice versa for cocaine. Chapter 3 illustrates the results of in which emotional imagery was combined with fMRI to investigation the neurobiological underpinnings of drug and setting interactions in addicts. Heroin and cocaine co-abusers were asked to recreate real-world settings of drug use during fMRI. In agreement with the working hypothesis, we found that heroin and cocaine imagery produced opposite changes in BOLD in the prefrontal cortex and in the striatum, regions implicated in brain reward in humans. Furthermore the same pattern of dissociation was observed in the cerebellum, suggesting that that a fronto-triatal-cerebellar network is implicated in processing drug-setting interactions. Chapter 4 includes a summary of the results, a general discussion, and suggestions for future research and implication. The major finding is that the environment surrounding drug use can influence in opposite manner the affective and neurobiological response to heroin and cocaine, suggesting that therapeutic approaches to the treatment of drug addiction should take into account the distinctive effects of different classes of drugs as well as the contexts of drug use. The Appendix includes reprints of two papers reporting on additional studies conducted during the course of the Ph.D. program, which are not directly germane to the aims of the dissertation. Other three papers are in the pre-submission stage.