The most evidence-based treatment for opioid dependence is opioid agonist maintenance treatment also known as opioid substitution therapy (OST). However, there are some critical, yet unaddressed issues of buprenorphine-based substitution therapy, especially in the Indian context. These comprise of generalizability of the evidence for OST, especially for natural and pharmaceutical opioids and for all age groups, optimum dose and duration of OST, and mode of treatment delivery including the frequency of dispensing. Notwithstanding the use of buprenorphine-naloxone combination, abuse and diversion are serious but often underreported problems. There is an urgent need for health services research in India on OST, focusing on these aspects. Rather than directly copying from Western models, it is important to try to understand the useful and safe program and policy options likely to be applicable in the Indian setting, with our own assets as well as vulnerabilities.