Substance use disorders are characterized by compulsive drug use and loss of control despite adverse consequences. This chapter reviews the neurobiological mechanisms underlying the progression from initial substance use to compulsive drug seeking and relapse. It begins with the description of the mesocorticolimbic dopamine system’s role in mediating pleasure and reinforcing effects of drugs, which contribute to initial drug use. Repeated exposure leads to neuroadaptive changes in the dopaminergic system, resulting in sensitization and increased motivational salience of drug-related cues. These changes cause a shift to a state of negative emotionality during withdrawal, known as “hedonic allostasis”, and contribute to compulsive drug seeking and relapse. The chapter also examines the impact of environmental cues on relapse, with evidence from animal models showing how exposure to drug-associated cues can reactivate neural ensembles and trigger cravings. The integration of theories such as the opponent process theory and behavioral sensitization helps elucidate the complex interactions between neurobiological changes and environmental factors in substance use disorders.