More than half of the cancer occurring today is preventable by applying knowledge that we already have. Tobacco, obesity, and physical inactivity are the modifiable causes of cancer that generate the most disease. Cancer burden can be reduced by alterations in individual and population behaviors and by public health efforts as long as these changes are driven by sound scientific knowledge and social commitment to change. The obstacles to these efforts are societal and arise from the organization of institutions, including academia, and in the habits of daily life. To achieve maximal possible cancer prevention, we will need better ways to implement what we know and improved infrastructure that will better incentivize and support transdisciplinary, multilevel research and successful intervention.