Outcome for children with acute lymphoblastic leukemia (ALL) has improved dramatically, with 5-year survival rates increasing from virtually nil in the early 1960s to approaching 90% by the first decade of the twenty-first century (Horner et al. 2009). While improvements in outcome have not been as impressive for children with acute myeloid leukemia (AML), 5-year survival rates have, nonetheless, increased to approximately 60% (Horner et al. 2009). These improvements are gratifying and represent tens of thousands of children diagnosed with leukemia over the last 20–30 years who have survived to adulthood. Looking forward, there are multiple challenges in study design and conduct in moving toward the goal of curing every child diagnosed with leukemia. These include identifying ways to make sound prioritization decisions about which new treatment approaches should be studied for specific patient populations and identifying ways to develop clinical trial datasets based on limited numbers of patients that allow sufficiently reliable conclusions to be drawn about the clinical benefit that these treatment approaches afford.