Relapse, a major obstacle in the treatment of acute leukemia, is essentially caused by re-growth of residual leukemia cells, frequently accompanied by resistance to chemotherapy. Comparative studies of clones both at initial diagnosis and at subsequent relapse have indicated that phenotype and karyotype are frequently changed at relapse. This can be recognized as the result of negative selection by chemotherapy in a heterogeneous population. Furthermore, complex molecular alterations that include the loss of as well as the acquisition of mutations are noticed by comparing multiple genes associated with leukemia, suggesting a continuous genetic evolution. Studies on leukemia relapse have thus served as a model of clonal progression, which can be serially observed, including selection by chemotherapy, induction of resistant phenotype, and genetic alteration.