The academic literature detailing escalations in pre-existing substance use practices is primarily understood through a biomedical lens, which situates drug escalation as a result of increases in biological markers like drug tolerance and dependence. This article seeks to frame the escalation of prescription drug misuse within a paradigm that situates drug use as a dynamic and interactional learning process shaped by set and setting. The data drawn upon for this article are derived from 41 qualitative interviews of young adults (aged 18–29 years) socially active in nightlife scenes who reported engaging in smoking prescription painkillers, sedatives, or stimulants. Results highlight how theories of drug use as a deviant behavior that is socially learned can be stretched beyond explaining patterns of initiation to also address the escalation of pre-existing drug use behaviors as users’ transition from one route of administration to another.