Childhood leukemia is the most common cause of malignancy under the age of 15, representing an annual incidence rate of 43 cases per million in the United States. Confirmed clinical and epidemiologic associations explain less than 10% of disease incidence, leaving 90% of cases with an unclear etiology. To effectively study leukemia in children, one must recognize that this disease has a multifactorial causal mechanism and a heterogeneous biological composition. In addition, the timing of environmental exposures and genetic changes related to disease risk must be considered. This review of both environmental and genetic risk factors for childhood leukemia evaluates the current published literature and synthesizes the available knowledge. Furthermore, attention is directed to expected sources of new advances and the compelling current issues that need to be addressed before further progress can be made. We discuss parental occupational exposures, air pollution, other chemical exposures such as household solvents and pesticides, radiation, dietary factors, immunological factors, socioeconomic status, and genetic susceptibility. We hope to provide the reader with an understanding of the challenge and promise that characterizes the current and future directions in childhood leukemia research.