Expanding on our previous analysis of Biomedical Informatics (BMI), the present perspective ranges from cybernetics to nanomedicine, based on its scientific, historical, philosophical, theoretical, experimental, and technological aspects as they affect systems developments, simulation and modelling, education, and the impact on healthcare. We then suggest that BMI is still searching for strong basic scientific principles around which it can crystallize. As -omic biological knowledge increasingly impacts the future of medicine, ubiquitous computing and informatics become even more essential, not only for the technological infrastructure, but as a part of the scientific enterprise itself. The Virtual Physiological Human and investigations into nanomedicine will surely produce yet more unpredictable opportunities, leading to significant changes in biomedical research and practice. As a discipline involved in making such advances possible, BMI is likely to need to re-define itself and extend its research horizons to meet the new challenges.