As increasing numbers of women with breast cancer survive their illness, it is critical to ascertain the long-term consequences of breast cancer treatment. One important effect is the occurrence of second malignancies, particularly in women treated with radiation therapy. Methodologic considerations raised in studying this issue include the effects of postmastectomy radiotherapy vs whole-breast irradiation, as currently employed following breast-conserving surgery; particularly germane are differences in the fields irradiated and the relative dosages to which various organs are exposed. Breast cancer radiotherapy does not appear to be a major factor in the occurrence of subsequent contralateral breast cancer. Such therapy may raise the risk of leukemia, particularly in association with certain types of adjuvant chemotherapy. Lung cancer risk is also increased, especially in cigarette smokers, and there are some indications that the risks of esophageal cancer and sarcomas may be elevated as well. Clinicians should be aware of these risks when trying to distinguish breast cancer recurrences from new primary malignancies. However, it should also be remembered that a high relative risk may represent only a slight increase in absolute risk. The benefits of breast cancer radiotherapy in improving survival or quality of life remain the principal factors to be weighed when deciding whether to treat patients with radiation.