Infections as well as environmental exposures are proposed determinants of childhood acute lymphoblastic leukemia (ALL), particularly common precursor B-cell ALL (cALL). Lines of investigation test hypotheses that cALL is a rarer result of common infection, that it results from uncommon infection, or that it ensues from abnormal immune development; perhaps it requires a preceding prenatal or early childhood insult. Ideally, studies should document that particular infections precede leukemia and induce malignant transformation. However, limited detection studies have not directly linked specific human or nonhuman infectious agents with ALL or cALL. Primarily based on surrogate markers of infectious exposure, indirect evidence from ecologic and epidemiologic studies varies widely, but some suggest that infancy or early childhood infectious exposures might protect against childhood ALL or cALL. Several others suggest that maternal infection during pregnancy might increase risk or that certain breast-feeding practices decrease risk. To date, evidence cannot confirm or refute whether at least one infection induces or is a major co-factor for developing ALL or cALL, or perhaps actually protects against disease. Differences in methodology and populations studied may explain some inconsistencies. Other challenges to proof include the likely time lag between infection and diagnosis, the ubiquity of many infections, the influence of age at infection, and the limitations in laboratory assays; small numbers of cases, inaccurate background leukemia rates, and difficulty tracking mobile populations further affect cluster investigations. Nevertheless, existing evidence partially supports plausibility and warrants further investigation into potential infectious determinants of ALL and cALL, particularly in the context of multifactorial or complex systems.