Despite the billions of health care dollars spent each year on treating skin cancer, there is a dearth of randomized controlled trials (RCTs) that have evaluated skin cancer prevention. RCTs published in the last 3 years that have directly assessed skin cancer prevention as their primary aim suggest that regular use of sunscreen is cost effective, but prolonged use of topical therapies such as tretinoin and 5-fluorouracil may not be. Sirolimus-based immunosuppression for secondary skin cancer prevention in long-term renal transplant recipients appears effective, but benefits may be offset by the adverse effects. Many RCTs using pre-invasive actinic keratoses (AKs) as endpoints are too small and/or too short to provide evidence on skin cancer prevention. Another stumbling block is the difficulty in reproducibly diagnosing and counting AKs in response to preventive agents. Longer term and better surveillance methods are urgently required to improve the quality of evidence from future RCTs.