The application of Information Technology (IT) to issues of healthcare delivery has had a long and tortuous history in the U.S. Within the field of eHealth, vanguard applications of advanced computing techniques, such as applications in artificial intelligence or expert systems, have languished in spite of a track record of scholarly publication and decisional accuracy. The problem is one of purpose, of asking the right questions for the science to solve. Historically, many computer science pioneers have been tempted to ask “what can the computer do?” New advances in eHealth are prompting developers to ask “what can people do?” How can eHealth take part in national goals for healthcare reform to empower relationships between healthcare professionals and patients, healthcare teams and families, and hospitals and communities to improve health equitably throughout the population? To do this, eHealth researchers must combine best evidence from the user sciences (human factors engineering, human-computer interaction, psychology, and usability) with best evidence in medicine to create transformational improvements in the quality of care that medicine offers. These improvements should follow recommendations from the Institute of Medicine to create a health care system that is (a) safe, (b) effective (evidence-based), (c) patient-centered, and (d) timely. Relying on the eHealth researcher’s intuitive grasp of systems issues, improvements should be made with considerations of users and beneficiaries at the individual (patient/physician), group (family/staff), community, and broad environmental levels.