Background Cancer is one of the leading causes of death within the United States. Adolescence remains a critical stage of development in which new cognitive skills and lifestyle factors related to cancer are acquired. It is critical to understand adolescents’ knowledge of cancer and preferences for receiving clear and easy-to-comprehend information about cancer and cancer prevention. The purpose of this study was to explore adolescents’ perceptions of cancer and cancer risk factors and identify their preferences for receiving cancer prevention education. Methods The survey used in this study was based on the Health Belief Model framework, the Youth Risk Behavior Survey, and the Cancer, Clear & Simple (CC&S) Curriculum. The survey evaluated adolescents’ knowledge, attitudes, and health-related behaviors regarding cancer and cancer prevention among adolescents. Three Midwestern middle and high schools were recruited, and 235 students completed the survey. Survey responses were analyzed using descriptive statistics. Results Study participants had some basic knowledge of cancer; however, only 66% recognized that individuals have control over their risk of developing cancer. Participants (95%) reported that cancer prevention was important, yet only 37.3% stated they knew how to lower their risk of getting cancer and 50% indicated that they currently try to make decisions that lower their chances of getting cancer. About 82% stated that an educational game would be a useful tool to learn about cancer and prevention. Conclusion Study findings indicate the need for an increase in adolescent knowledge of cancer, specifically how they can control their cancer risk, and prevention strategies through development of game-based education to teach adolescents about cancer-related topics.