Web-based behavioral intervention research is rapidly growing. We review methodological issues shared across Web-based intervention research to help inform future research in this area. We examine measures and their interpretation using exemplar studies and our research. We report on research designs used to evaluate Web-based interventions and recommend newer, blended designs. We review and critique methodological issues associated with recruitment, engagement, and social validity. We suggest that there is value to viewing this burgeoning realm of research from the broader context of behavior change research. We conclude that many studies use blended research designs, that innovative mantling designs such as the Multiphase Optimization Strategy and Sequential Multiple Assignment Randomized Trial methods hold considerable promise and should be used more widely, and that Web-based controls should be used instead of usual care or no-treatment controls in public health research. We recommend topics for future research that address participant recruitment, engagement, and social validity.