Regimens of adjuvant chemotherapy for early-stage breast cancer commonly include alkylating agents and anthracyclines. These agents have been associated with treatment-related acute myelocytic leukemia (AML) or myelodysplastic syndrome (MDS). This article reviews the medical literature concerning the incidence, causes, and natural history of treatment-related AML/MDS, with emphasis on the association of these factors with alkylating agents, topoisomerase inhibitors, growth factors, and radiation treatment. Data from 6 completed adjuvant National Surgical Adjuvant Breast and Bowel Project trials that tested regimens containing doxorubicin and cyclophosphamide were reviewed to characterize the incidence of treatment-related AML/MDS. The regimens differed in cyclophosphamide intensity, cumulative cyclophosphamide dose, and the presence or absence of mandated prophylactic support with growth factor and ciprofloxacin. Rates were compared across regimens, by patient age, and by treatment with or without adjuvant in-breast radiation therapy (RT). The relative risk (RR) for the development of treatment-related AML/MDS was greater for patients undergoing the more-intense regimens than for those undergoing standard AC (doxorubicin/cyclophosphamide) regimens (RR, 6.16; P<0.0001). Risk correlated more closely with dose intensity than with cumulative dose, and the data suggested that granulocyte colony-stimulating factor (G-CSF) dose may also be independently correlated with increased risk. Patients who received in-breast RT experienced more secondary AML/MDS than those who did not (RR, 2.38; P=0.006). Patients treated with AC with intensified doses of cyclophosphamide requiring G-CSF support had increased rates of treatment-related AML/MDS, even though the incidence was slight relative to breast cancer relapse. In-breast RT appeared to be associated with an increased risk of AML/MDS.