Cancer is a general term of a series of complex traits of the disease triggered by the body cells losing their normal regulation of excessive proliferation, which essentially is a genetic disease. Recombinant inbred strain (RI) mouse generated from one pair of founders has been widely used in traditional tumor model. However, RI has many limitations on the statistic efficiency because of the small scale and lacking of allele diversity. The Collaborative Cross (CC) was designed to generate hundreds of recombinant inbred lines by 8 divergent strains of mice. CC mice embody a tremendous amount of natural genetic variation in different sub-strains of mouse and the single nucleotide polymorphism is four times of the traditional experimental mice. The high-genetic diversity and large scale population enables CC mice simulates the differences of individual susceptibility to the pathogeny or the therapies,thus provides a better research tool and information platform for expediting discovery of genes and genes function in human complex traits diseases. This review summarizes our current knowledge of this field, including methodologic aspects, applications, challenges and limitations, and utilization for cancer research.