This study documents our experience in designing, testing, and refining human subjects' consent protocol in 3 of the first NIH-funded online studies of HIV/STI sexual risk behavior in the USA. We considered 4 challenges primary: a) designing recruitment and enrollment procedures to ensure adequate attention to subject considerations; b) obtaining and documenting subjects' consent; c) establishing investigator credibility through investigator-participant interactions; d) enhancing confidentiality during all aspects of the study. Human consent in online studies appears more relative, continuous, inherent, tenuous, and diverse than in offline studies. Reasons for declining consent appear related to pragmatic concerns not human subjects' risks. Reordering the consent process, and short, chunked, stepwise, tailored consent procedures may enhance communicating information and documenting consent.