In the past 2 decades, the demand for information on health economics research to guide health care decision making has substantially increased. Studies have provided evidence that eliminating or reducing tobacco use; eating a healthy diet, including fruit and vegetables; being physically active; reducing alcohol consumption; avoiding ultraviolet radiation; and minimizing exposure to environmental and occupational carcinogenic agents should substantially reduce cancer incidence in the population. The benefits of these primary prevention measures in reducing cancer incidence are not instantaneous. Therefore, health economics research has an important role to play in providing credible information to decision makers on the health and economic benefits of primary prevention. This article provides an overview of health economics research related to primary prevention of cancer. We addressed the following questions: 1) What are the gaps and unmet needs for performing health economics research focused on primary prevention of cancer? 2) What are the challenges and opportunities to conducting health economics research to evaluate primary prevention of cancer? and 3) What are the future directions for enhancing health economics research on primary prevention of cancer? Modeling primary prevention of cancer is often difficult given data limitations, long delays before the policy or intervention is effective, possible unintended effects of the policy or intervention, and the necessity of outside expertise to understand key inputs or outputs to the modeling. Despite these challenges, health economics research has an important role to play in providing credible information to decision makers on the health and economic benefits of primary prevention of cancer.