Highly active antiretroviral therapy (HAART) has dramatically improved health outcomes among people living with HIV/AIDS. However, significant rates of HIV-related morbidity and mortality have persisted among HIV-positive injection drug users (IDU) globally. To date, research as well as programmatic and policy responses have failed to adequately address barriers to HAART access and adherence among IDU both in developing/transitional and developed countries. A review of existing literature suggests that this is due to a shortage of context-specific evidence and an overemphasis on individual-level and behavioural variables. We propose a conceptual shift away from understanding suboptimal HAART adherence as determined predominantly by individual factors modifiable through individually focused interventions, towards a greater acknowledgement of the influence of social and structural factors such as stigmatization and social exclusion, unstable housing environments, the organization of health care systems and the continued prohibitionist approach to illicit drug policy. Globally, the future of a successful HAART treatment approach for HIV-positive IDU relies largely on a more careful consideration of these social and structural barriers that IDU face and, importantly, on a serious commitment to effect social and structural changes that will foster conditions which allow IDU to enjoy the full benefits of HAART.