Misuse of prescription drugs and injection drug use has increased among young adults in the USA. Despite these upward trends, few studies have examined prescription drug misuse among young injection drug users (IDUs). A qualitative study was undertaken to describe current patterns of prescription drug misuse among young IDUs. Young IDUs aged 16-25 years who had misused a prescription drug, e.g., opioids, tranquilizers, or stimulants, at least three times in the past 3 months were recruited in 2008 and 2009 in Los Angeles (n = 25) and New York (n = 25). Informed by an ethno-epidemiological approach, descriptive data from a semi-structured interview guide were analyzed both quantitatively and qualitatively. Most IDUs sampled were both homeless and transient. Heroin, prescription opioids, and prescription tranquilizers were frequently misused in the past 30 days. Qualitative results indicated that young IDUs used prescription opioids and tranquilizers: as substitutes for heroin when it was unavailable; to boost a heroin high; to self-medicate for health conditions, including untreated pain and heroin withdrawal; to curb heroin use; and to reduce risks associated with injecting heroin. Polydrug use involving heroin and prescription drugs resulted in an overdose in multiple cases. Findings point to contrasting availability of heroin in North American cities while indicating broad availability of prescription opioids among street-based drug users. The results highlight a variety of unmet service needs among this sample of young IDUs, such as overdose prevention, drug treatment programs, primary care clinics, and mental health services.