In this monograph, I discuss evidence which suggests that childhood leukemia originates in utero. Furthermore, in some cases, especially those with MLL gene rearrangement (MLL+), exposure to some particular environmental toxic factors appears to increase the risk of leukemia. This exposure, together with a genetic background of genomic instability or defects in detoxifying environmental factors, may increase the risk of childhood leukemia. In light of these findings, future study should include the identification of risk factors in environmental and genetic stresses. By identifying the genetic characteristics of individuals, we can provide proper environment including maternal conditions with pregnancy. Understanding the genetic and environmental basis of childhood leukemia is a prerequisite to overcome the risks for the development of this intractable childhood disease in the future.