A critical overview of recent clinical trials in cancer is presently focused on signaling pathway blockers or inhibitors with a view to developing successful clinical trials employing personalized cancer therapies. Rational, pharmacogenomic strategies in cancer trials should be adopted that include specific molecular targeting based on adequate data for, and detailed modeling of, cancer cell genomes, modifications of cancer signaling pathways and epigenetic mechanisms. Novel translational oncogenomics research is rapidly expanding through the application of highly sensitive and specific advanced technology, research findings and computational tools and complex models to both pharmaceutical and clinical problems. Multiple sample analyses from several recent clinical studies have shown that gene expression data for cancer cells can be employed to distinguish between tumor types as well as to predict outcomes. Potentially important applications of such results are individualized human cancer therapies or, in general, ‘personalized medicine’ that will have to be validated through optimally designed clinical trials in cancer. A Human Cancer Genomes and Epigenetics Project is proposed that can provide the essential data required for the optimal design of clinical trials with the goal of achieving significant improvements of the survival rates of cancer patients participating in clinical trials for advanced cancer stages. The results of such a six-year Human Cancer Genomes and Epigenetics Project should also greatly aid with the accelerated, rational development of effective anti-cancer medicines and the chemoprevention of cancers.