Childhood leukemia is a biologically and clinically diverse disease and is likely to arise via a number of etiological pathways. The common, B-cell precursor, form of acute lymphoblastic leukemia (cALL) accounts for the peak of childhood leukemia at 2-5 years of age. Recent epidemiological data, reviewed here, indicate that risk of cALL is increased by higher socio-economic status, isolation, and other community characteristics suggestive of abnormal patterns of infection during infancy. These data are compatible with the emerging concept that cALL may be a rare response to common infection(s).