The global cancer burden continues to rise and the war on cancer can only be won if improvements in treatment go hand in hand with therapeutic cancer prevention. Despite the availability of several efficacious agents, utilisation of preventive therapy has been poor due to various barriers, such as the lack of physician and patient awareness, fear of side effects, and licensing and indemnity issues. In this review, we discuss these barriers in detail and propose strategies to overcome them. These strategies include improving physician awareness and countering prejudices by highlighting the important differences between preventive therapy and cancer treatment. The importance of the agent–biomarker–cohort (ABC) paradigm to improve effectiveness of preventive therapy cannot be overemphasised. Future research to improve therapeutic cancer prevention needs to include improvements in the prediction of benefits and harms, and improvements in the safety profile of existing agents by experimentation with dose. We also highlight the role of drug repurposing for providing new agents as well as to address the current imbalance between therapeutic and preventive research. In order to move the field of therapeutic cancer prevention forwards, engagement with policymakers to correct research imbalance as well as to remove practical obstacles to implementation is also urgently needed.