Although studies on the initiation of substance abuse abound, the body of literature on prescription opioid abuse (POA) etiology is quite small. Little is known about why and how the onset of POA occurs, especially among high risk drug using populations. The present study aims to fill this important knowledge gap by exploring the POA initiation experiences of 90 prescription opioid abusers currently in treatment and their narrative accounts of the circumstances surrounding their POA onset. Audiotapes of in-depth interviews were transcribed, coded, and thematically analyzed using the NVivo software program. This research was conducted within a storylines framework, which operates on the premise that the path to drug abuse represents a biography, or a process, rather than a static condition. Analysis revealed the presence of four trajectories leading to POA. The first pathway to POA, the South Florida Effect, highlighted the role that the local “pill culture” can play in influencing the formation of POA, while the second focused on females who initiate their POA through the help of an abusing male. The third, or the Cocaine Context, describes an entryway into POA via the world of cocaine. The final POA trajectory, Prescribed Addiction, reveals how users who are prescribed opioids can fall into problems with POA. This study adds to the dearth of research on POA etiology by not only illuminating the psycho-social factors that contribute to POA onset, but also by situating initiation experiences within broader life processes. While some of these findings support previous research, others alter the manner in which POA etiology should be viewed. This study expands current notions of POA initiation by providing clear and detailed descriptions of the circumstances and events that can lead to POA. These findings provide crucial insights to policymakers and interventionists in identifying who is at risk for POA, and more importantly when and how to intervene most efficaciously.