Applied research in HIV prevention with out-of-treatment substance abusers takes place in a constantly changing environment. Researchers must be able to identify changes in drug use and sexual risk patterns, develop and evaluate appropriate interventions to respond to those changes, and find ways to make effective use of new technologies as they are developed. An example of this process is the collaborative revision made to NIDA's Standard Intervention for HIV prevention by the final six study sites funded under the NIDA Cooperative Agreements for AIDS Community-Based Outreach and Intervention Research. To illustrate the process of responding to changes in the substance abuse environment, to advances in knowledge about risk, and to newer technologies, this article provides an overview of the history of two federally funded HIV-prevention programs for out-of-treatment substance abusers and reviews recent changes made to the Standard Intervention protocol. The rationale for the changes is discussed, and the substance abuse population in the study is described.