Myeloid malignancies frequently harbor specific mutations in protein tyrosine kinases leading to oncogenic cellsignaling. The most extensively investigated example is chronic myeloid leukemia, where the pathogenic tyrosine kinasefusion protein Bcr-Abl is a successful target for disease control by the specific inhibitor imatinib mesylate. In acute mye-loid leukemia the receptor tyrosine kinase Flt3 is frequently mutated and inhibitors to impair the oncogenic signaling arein development. In this review we exemplify oncogenic signaling and how signal pathways can be unraveled with helpfrom proteomics-based technologies. The distinction between cell extract and single cell approaches aiming at rigorousstandardization and reliable quantitative aspects for future proteomics-based diagnostics is discussed.