Acute lymphoblastic leukemia (ALL) is predominantly a disease of the bone marrow that disseminates to multiple organ sites throughout the body and, without aggressive treatment, eventually results in multiorgan failure and death. Experimental models that mimic the dissemination of ALL have been difficult to establish, principally due to the poor engraftment efficiency of normal and malignant human hematopoietic cells in various strains of immune-deficient mice. The recent availability of mouse strains that are even more immunocompromised than established strains such as the nude (nu/nu) or severe combined immunodeficient (SCID) mouse has presented opportunities to establish improved experimental models of human leukemia. In this chapter we outline the methodology to (1) establish continuous xenografts from primary childhood ALL biopsies in nonobese diabetic/SCID (NOD/SCID) mice and (2) utilize these xenograft models of systemic disease to test established and experimental drugs while monitoring leukemia progression in "real time" by serial monitoring of murine peripheral blood. These experimental models will be useful for the preclinical evaluation of novel therapies.