The aim of this paper is to advance rigorous Internet-based HIV/STD Prevention quantitative research by providing guidance to fellow researchers, faculty supervising graduates, human subjects’ committees, and review groups about some of the most common and challenging questions about Internet-based HIV prevention quantitative research. The authors represent several research groups who have gained experience conducting some of the first Internet-based HIV/STD prevention quantitative surveys in the US and elsewhere. Sixteen questions specific to Internet-based HIV prevention survey research are identified. To aid rigorous development and review of applications, these questions are organized around six common criteria used in federal review groups in the US: significance, innovation, approach (broken down further by research design, formative development, procedures, sampling considerations, and data collection); investigator, environment and human subjects’ issues. Strategies promoting minority participant recruitment, minimizing attrition, validating participants, and compensating participants are discussed. Throughout, the implications on budget and realistic timetabling are identified.