Earlier in the past century, infections were regarded as the most likely cause of childhood B-precursor acute lymphoblastic leukemia (pB-ALL). However, there is a lack of relevant biological evidence supporting this hypothesis. We present in vivo genetic evidence mechanistically connecting inherited susceptibility to pB-ALL and postnatal infections by showing that pB-ALL was initiated in Pax5 heterozygous mice only when they were exposed to common pathogens. Strikingly, these murine pB-ALLs closely resemble the human disease.