This study examines patterns of use of prescription drugs and methamphetamine. We drew our sample from a study about 130 active and inactive methamphetamine users and focused on 16 participants with a recent history of methamphetamine and prescription drug use. We collected in-depth interviews to explore relationships in use trajectory patterns. The qualitative methods we used in this study followed the constant comparison process developed by grounded theory methods and analytical ethnography, which is based on familiarity with the social setting and developing propositions while conducting a research study. We used a triangulation of methods and analysis and included qualitative data, such as participant observation notes and in-depth interviews, as well as quantitative data that we collected in drug history matrices. Five themes emerged from the coding of the interview transcripts: (1) sequential polydrug use; (2) concurrent polydrug use (3) temporary substitution of preferred drug; (4) consequential-based use; and (5) switching from using methamphetamine to using prescription drugs. The trajectory patterns of methamphetamine and prescription drug use complicates treatment significantly.