Just over 10 years have passed since public health experts called for an update to the "infection risk reduction hierarchy". At the time Vlahov et al. noted that HIV prevention programs for people who inject drugs (PWID), 13% of whom are estimated to be HIV positive, should include referral to addiction treatment, increased access to sterile syringes, and education regarding the harms of syringe sharing, given that all had been proven effective at reducing the spread of injection-related HIV transmission. However, while these interventions are critical to reducing the burden of HIV faced by active injectors, they also argued that the most effective method of preventing injection-driven HIV epidemics was to shift resources upstream, towards the prevention of injection drug use itself. Since the publication of this commentary, expanded coverage of harm reduction services and the provision of sterile injecting equipment have resulted in reductions in HIV transmission among PWID in select settings. However, blood-borne disease epidemics continue to expand among PWID populations; for example, according to UNAIDS, HIV infections among PWID increased by 33% globally between 2011 and 2014. Concurrently, fatal drug overdose (often related to opioid injecting) has become a leading cause of death in both the USA and Canada. We therefore seek to assess the state of the science on the prevention of injection initiation, to identify emerging interventional strategies, and to consider the barriers that remain in effectively controlling ongoing epidemics of injection drug use. [Extract]