This paper examines the changes that have occurred in methadone maintenance programmes in response to the advent of HIV and the adoption of harm minimization policies, and the implications of these changes for research. A need for the use of more rigorous research methods is identified and recommendations are made that take into account both the ethical and practical difficulties of conducting research in this area. Both old, unanswered questions that have resurfaced with the recent massive growth in methadone programmes in some countries, and new questions that need to be answered in order to improve the effectiveness of methadone maintenance in the fight against HIV infection are identified as future areas in need of research.