In 1971, when Congress declared “war on cancer,” the public's perception was driven by an image of a single cure for a single disease. What researchers have learned since that time is that cancer is a formidable enemy made up of more than 100 different disease etiologies. The war on cancer became a war of the 21^st century; a war to be fought on multiple fronts against a diffuse enemy and for which prevention was the most judicious path to victory. To fight this new war on cancer, the National Cancer Institute must seek to harness the power of health informatics to create a supportive environment for transforming science, delivering safe and patient-centric health care, and creating an environment of personal empowerment in public health. Three different types of health informatics applications are implicated: (a) applications in bioinformatics, which are intended to revitalize the engine of scientific discovery; (b) applications in medical informatics, which will create a safer and more effective environment for delivery; and (c) applications in consumer informatics, which will enable individuals to advance the charge of their own ongoing health care over the course of their lives. To keep these applications on track, health care administrators must take a sociotechnical approach to implementation. The new systems must be built into the health care environment in such a way that they support human capacities, provide failsafe backups in the face of cognitive and physical limitations, and support continuous quality improvement.