Elimination of solid tumors refractory to the standard approaches is a significant challenge. The hypothesis that cancer stem cells (CSC) are responsible for the resistance to treatment, require novel therapies for cancer. Although recent studies determined phenotypes associated with CSC in distinct tumors, therapeutics lags behind. It is possible that the originally described CSC contain cells in different stages of differentiation and in different phases of the cell cycle. Most CSC should be sensitive to current treatment with enzyme inhibitors (PI3K, HDAC, PARP). In some patients, tumors recur after long periods (20-24 months) of disease free life. Novel molecular therapies, with inhibitory RNA or metastasespreventive vaccine are needed for patients which develop metastases originating from small numbers of cancer cells undetectable at the time of cure. We hypothesize that a common denominator of molecular therapies against CSC is the need for two agents: one, (available) which inhibits cell-cycle progression and a second, (to be developed) which kills “resting“ CSC.