Humans form powerful associations between drug-taking experiences and the physical environment that surrounds their drug use through a process called contextual conditioning. These drug-associated environments can reinforce drug-taking behavior, and in many cases, can cause a drug addict to relapse, even after years of abstinence. Because of this, contextual conditioning plays a key role in the study of addiction. In animals, drug-associated environments promote the reinstatement of drug-seeking, as well as elicit a range of behavioral and physiological reactions that predict relapse. In clinical settings, empirical and anecdotal evidence show the powerful effect of drug-associated contexts on drug cravings, and also suggest that humans vary in their susceptibility to relapse. However, little is known about how these drug-environment associations develop in humans, and what factors underlie variability in how contextual conditioning is acquired. In animals, the acquisition of contextual conditioning is studied using the conditioned place preference paradigm, wherein animals receive a reward, such as a drug, consistently in the same environment, and it is tested whether they develop a behavioral preference for the reward-paired environment (i.e. whether they spend more time in that environment) over time. Very few human conditioned place preference studies have been completed using drugs of abuse; therefore, it is critical that more controlled studies of contextual conditioning to drug-associated environments take place. Human conditioned place preference studies can help elucidate the subjective, behavioral, and physiological mechanisms that underlie individual differences in the acquisition of contextual conditioning., The purpose of the first study in this dissertation (Study 1) was to replicate a previous human conditioned place preference study, which used an amphetamine reward, and measured preference using self-reports of explicit room preference. In addition, we aimed to determine whether humans would spend more time in a room in which they previously received AMP after the pairings than beforehand, like in the animal CPP paradigm. We gave healthy human volunteers 20mg of amphetamine and placebo twice each in either of two rooms. One group (the Paired Group) consistently received amphetamine in one room and placebo in the other room, while the Unpaired Group received amphetamine and placebo in both rooms. We examined the change in preference for the two rooms using both objective and subjective measures. Before and after conditioning, subjects explored the two conditioning rooms for ten minutes, and we measured how much time the spent in each room. We also had them rate on a questionnaire how much they liked and preferred each room. Following conditioning, subjects in the Paired Group demonstrated a significant increase in liking and preference for the amphetamine-paired environment, but they did not exhibit an increase in time spent in that environment. We also found that the degree of subjective conditioning correlated with the magnitude of the subjects’ “liking” of the drug. Here, we successfully replicated the subjective preference measures seen previously in humans, but we were unable to reproduce the time spent measure that is used in animals., Next, in Study 2, we aimed to determine individual differences in the acquisition of conditioning in Study 1, in combination with the study it replicated. Here, we sought to find out whether personality predicts amphetamine conditioned place preference, and whether personality moderates the relationship between the positive subjective effects of amphetamine and conditioning. Here, we found that Positive Emotionality predicted the increase in subjective preference for the amphetamine-paired, but that Negative Emotionality did not. We also found that amphetamine-induced euphoria predicted conditioning, but that neither Positive Emotionality nor Negative Emotionality moderated the relationship between amphetamine-induced euphoria and conditioning. This analysis demonstrated for the first time that personality predicts conditioned place preference in humans, and that this relationship is independent of the subjective effects of amphetamine., Finally, because we were unable to elicit an objective place preference in Study 1, we sought to expand and refine our amphetamine conditioning place preference paradigm with the hope of inducing an objective preference for the amphetamine-paired room (Study 3). In this study, we aimed to determine the optimal number of conditioning sessions for inducing the strongest place preference. Secondarily, we aimed to study the subjective, behavioral, and physiological effects of the amphetamine-paired room. Here, all subjects underwent eight conditioning sessions. Paired Group subjects underwent four amphetamine-room pairings, and both groups’ subjective and objective preferences for the rooms were measured after two, four, and eight conditioning sessions. Additionally, we measured mood, heart rate, blood pressure, and autonomic nervous system activity during the conditioning sessions as well as after conditioning. In this study, despite experiencing the prototypical acute subjective and physiological responses to the drug, subjects in the Paired Group did not express an increase in subjective or objective preference for the amphetamine-paired room after any number of drug-room pairings. Also, subjects did not express conditioned increases in the subjective, behavioral, or physiological responses to the drug in the drug-paired environment, or to the drug-paired room in the absence of drug. In this chapter, we discuss the potential implications of the study design on the study’s outcome., The studies presented here provide further evidence that humans will develop a subjective preference for an amphetamine-paired room, but they also demonstrate that this paradigm requires further refinement and expansion. First, we demonstrated the reliability of subjective measures of contextual conditioning in humans. Second, we also showed that this preference is related the subjective effects of amphetamine and personality. Finally, our last study demonstrates the sensitivity of contextual conditioning to parametric changes in the protocol, and therefore, that more steps must be taken to optimize this paradigm. These studies provide a basis for future research into how drug-environment associations develop in humans and what individual differences underlie the susceptibility to acquiring contextual conditioning.