In clinical terms, all human cancers diagnosed in individuals can be divided in two major categories: malignant tumors that will be cured with the existing cancer therapies and tumors that have therapy-resistant phenotypes and will return after initial treatment as incurable metastatic disease. These tumors manifesting clinically lethal death-from-cancer phenotypes represent the most formidable challenge of experimental, translational, and clinical cancer research. Clinical genomics data demonstrate that gene expression signatures associated with the "stemness" state of a cell are informative as molecular predictors of cancer therapy outcome and can help to identify cancer patients with therapy-resistant tumors. Here, we present experimental and clinical evidence in support of the BMI1 pathway rule indicating a genetic link between the stemness state and therapy-resistant death-from-cancer phenotypes. Our analysis demonstrates that therapy-resistant and therapy-responsive cancer phenotypes manifest distinct patterns of association with stemness/differentiation pathways, suggesting that therapy-resistant and therapy-responsive tumors develop within genetically distinct stemness/differentiation programs. These differences can be exploited for development of prognostic and therapy selection genetic tests utilizing a microarray-based cancer therapy outcome predictor algorithm. One of the major regulatory pathways manifesting distinct patterns of association with therapy-resistant and therapy-responsive cancer phenotypes is the Polycomb group proteins chromatin silencing pathway.