Somatically acquired genomic alterations have been recognized as key hallmarks inducing acute lymphoblastic leukemia (ALL), though recent knowledge acquired from genome-wide association study (GWAS) has revealed that inherited genetic variations (germline) are associated with ALL susceptibility as well as disease onset. The proportion of ALL cases attributable to an inherited genetic predisposition has been recognized as being much higher in clinical practice than previously thought since familial cases with hematopoietic transcriptional factors (PAX5 and ETV6) were reported. Considering the characteristics related to inherited variants, issues associated with these variants persist from childhood throughout the patient's entire life, and specific approaches to both familial ALL cases and carriers with inherited variants are thus urgently needed. This review focuses on familial ALL caused by the two aforementioned transcriptional factors (PAX5 and ETV6).