As we begin the fourth decade of the epidemic, it is clear that, as demonstrated by the articles in this Special Issue, much has been learned about factors contributing to the decline in HIV prevalence among drug users in New York. However, there are a number of outstanding research questions that remain or are emerging. Following is a summary of some of the topics requiring further research. While this summary does not represent a comprehensive list, it is based on many of the questions raised in the articles in this Special Issue and identifies some of the directions to be investigated during the next decade.