The present invention relates to a system of multi-stage stem cell carcinogenesis and a method of generating such multi-stage stem cell carcinogenesis system. Various stages of cancer stem cells can be generated from normal stem cells via mutagenesis. The system of the present invention enables monitoring changes in the ability of cells to transition from one stage of carcinogenesis to another and to identify genetic pathways and molecules that influence carcinogenesis. The present invention also enables a high-throughput and nonbiased screening for targets that preferentially affect cancer stem cells relative to non-cancer stem cells or their derivatives during stem cell carcinogenesis, thus is useful in developing anti-cancer therapeutics.