More and more potent therapeutic approaches demand more and more sophisticated response monitoring. Soon after the introduction of the first tyrosine-kinase inhibitor (TKI) for chronic myeloid leukemia (CML) treatment, real time quantitative polymerase chain reaction (RQ-PCR) became the gold standard to follow the kinetics of reduction of disease burden and allow prognostic stratification. Continuous therapeutic improvement has led to increasingly ambitious treatment endpoints (now culminating in the possibility of achieving treatment free remission), which, in turn, has led to more and more refined measurement and definition of molecular response (MR) levels. Here, we will review the evolution of molecular response definitions and terminology, how specific MR levels currently provide key checkpoints in the context of optimal patient management, how molecular monitoring can best be performed nowadays and what future trends for further technological improvement can be.