In this Rube Goldberg contraption, leukemic cells are entered at the “Start” arrow, treated with an azanuceloside analog, and emerge as normal neutrophils. Along the way, a variety of epigenetic targets and DNA damage and repair pathways are encountered. Klco et al illustrate that despite state-of-the-art genomic technology, the mechanisms accounting for the clinical activity of DNMT inhibitors in myeloid leukemias remain complex and unclear.