An estimated 10% of acute leukemias carry mixed-lineage leukemia (MLL) fusion genes. Approximately 50 different fusion partners of the MLL gene have already been molecularly identified. These leukemias are commonly regarded as high-risk cases and are treated accordingly with intensified therapy regimens, including hematopoietic stem cell transplantation. However, a subset of patients may achieve long-term remissions with conventional therapy. Monitoring minimal residual disease (MRD) is undoubtedly of great value in clinical decision making, also in the pre- and post-transplant setting. Here, we describe a novel method for detecting MRD in leukemias with MLL aberrations. The method is based on monitoring patient-specific chromosomal breakpoint DNA sequences. This has several advantages over other methods that are based either on detecting specific RNA molecules of MLL fusion genes or on surrogate markers. An accurate and absolute quantification of the MRD level is possible. No reference to housekeeping genes is necessary and the target structure is much more stable than any mRNA fusion transcript.