Technology-enabled HIV research and prevention has emerged in the past 10 years as an exciting dynamic field that offers great potential to help bring HIV prevention efforts to scale in key risk communities. Evolutions in technologies and in HIV epidemics suggest mutual opportunities to reach most at risk populations in novel ways. New technologies cannot completely replace interventions and services currently delivered by the people. However, we suggest that emerging technologies hold promise to bring services to scale and produce efficiencies in reaching rural populations of men who have sex with men (MSM), connecting with populations who are not reached in current urban outreach efforts, and providing services or research surveys that can be described algorithmically. Furthermore, the types of technologies (eg, internet-based, smartphone-based, text messaging) should be matched with both the content to be delivered and the technology usage patterns of target populations. We suggest several key principles and lessons learned that comprise a framework in which to consider the opportunities of technologies and HIV prevention and research. Future directions include improvement of data quality in online surveying, better characterization of biases, developing improved sampling approaches, working with funders to ensure compatibility of funding mechanisms and online research proposals, and promoting consensus approaches to the duplication and presentation of research and program evaluation results from online research. Given the current calls for comprehensive packages of prevention services for MSM, effective prevention might require an intentional combination of technology-enabled prevention services to achieve scale and strategic use of personally delivered package components in cases where non-algorithmic services, such as individualized counseling, are needed.