Evolution requires change but the field of toxicology has not kept pace. The top ten problems urging change are: 1) disparity of testing requirements and risk acceptance for different products and geographical areas; 2) throughput and testing costs versus testing needs; 3) limited predictivity for humans; 4) precautionary approaches from drug development adapted to other areas; 5) animal use; 6) traditional tests unsuitable for new products; 7) lack of coverage for new hazards; 8) failure to address mixtures of toxicants; 9) lack of coverage for individual susceptibilities and vulnerable subpopulations; 10) poor basic research and publication standards. The intransigence at the root of these problems is discussed with reference to current international toxicological policies and methods. For each, the limitations are reviewed with reference to key literature. While current approaches are still needed, there is room for substantial change. To meet the challenges of the 21st century, revolution rather than evolution is required.