The aetiology of leukaemias among children is believed to be distinct from that of adults, mainly due to the clearer role for early life exposures, including those in utero. However, few risk factors have been established, because of the challenge of studying a disease with relatively low incidence. Identified risk factors, including ionizing radiation, chemotherapeutic agents and specific genetic abnormalities, explain < 10% of incidence. Although the causes for the remaining 90% are unknown, it is possible that genetic susceptibility factors, either alone or in conjunction with environmental factors, may be involved. In this paper, the authors (a) review the evidence surrounding genetic susceptibility factors, with emphasis on the genes' main effects; (b) review some recent developments in the Northern California Childhood Leukaemia Study (NCCLS) as a case study of design and practical considerations in genetic epidemiology research and (c) highlight both challenges and future directions in this exciting research area.