Recent North American data suggest that the misuse of prescription opioids (POs) has substantially increased in segments of the general population (e.g., adults, youth, students), as well as in specific high-risk groups (e.g. street drug users), in many instances surpassing prevalence rates for traditional illicit drugs. Some 11 million U.S. citizens are estimated to have misused POs in 2002 alone. These misuse trends have corresponded with increases in PO-related harms, i.e. morbidity (e.g., emergency room mentions) and mortality (e.g., poisoning deaths). Existing data suggest that POs for misuse are obtained from a diverse variety of sourcing routes, many of which involve direct or indirect diversion from the medical system, yet also include personal contacts, thefts or street markets. The above is occurring in a recent context of massively increased medical availability and use of POs, mainly due to changes in pain treatment practice, with North America being the world's top PO consumer region. The intersecting of legitimate and illegitimate PO use poses enormous challenges for devising control interventions that effectively address the problem of PO misuse while not compromising adequate pain care. Current interventions include intensified PO availability regulation by prescription monitoring programs (PMPs). This article reviews available (mainly North American) data describing the phenomenon of PO misuse, while considering policy implications.