The use of combination chemotherapy to cure acute lymphoblastic leukemia in children and acute myeloid leukemia in adults emerged for acute myeloid leukemia in the 1960s and for acute lymphoblastic leukemia in the 1980s as a paradigm for curing any disseminated cancer. This article summarizes recent developments and considerations in the use of acute leukemia xenografts established in immunodeficient mice to elucidate the genetic and genomic basis of acute leukemia pathogenesis and treatment response.