Treatment of patients with acute leukemia is based on antineoplastic drug therapy (mainly chemotherapy) and/or immunotherapy, such as allogeneic stem cell transplantation, both associated with the risk of severe toxicity, including treatment-related mortality. Therefore, the extent of therapy should ideally be adapted to the patient’s individual relapse risk. The latter can be estimated taking into account leukemia subtype as well as conventional and molecular cytogenetics, as determined at the time of diagnosis. Furthermore, particularly in acute lymphoblastic leukemia (ALL), early and subsequent assessment of treatment response is routinely incorporated into the global risk stratification. Multiparameter flow cytometry and molecular methods allow for the detection of minimal residual disease that remains obscure to conventional cytology. While molecular monitoring of the treatment efficacy has entered clinical routine in chronic myelogenous leukemia, acute promyelocytic leukemia and ALL, this concept is still evolving in acute myeloid leukemia. This short review is aimed to give an overview of current methods as well as established and candidate indications of molecular disease monitoring in patients with acute leukemia.