Breast irradiation, adjuvant chemotherapy, and tamoxifen are associated with an increased risk of second cancers that may manifest decades after treatment. Although very small, it is nonetheless important for clinicians and women to be aware of and to recognize the risk. Postmastectomy irradiation is associated with a slight increase in the risk of developing a sarcoma or lung cancer after a latency period of more than 10 years. However, the majority of information on radiation-associated cancers is derived from large tumor registries, which reflect outdated radiation treatment practices. Modern treatment approaches, which use lower fraction size (or dose) and limit the exposure of surrounding normal tissue to radiation, are less likely to cause radiation-associated cancers. Adjuvant chemotherapy is not associated with any detectable increased risk of solid tumors beyond that which occurs as the population ages. However, alkylating agents, such as cyclophosphamide, and the topoisomerase II inhibitors, doxorubicin and epirubicin, are associated with two types of cytogenetically distinct leukemias after adjuvant chemotherapy. The absolute risk of developing leukemia is lower by orders of magnitude than the improvement in breast cancer mortality that results from adjuvant chemotherapy. Tamoxifen is associated with a two- to threefold increase in the risk of developing endometrial cancer, or about 80 excess cases per 10,000 treated women at 10 years. The benefits of adjuvant therapy outweigh the risks of developing second cancers. Additional studies are needed to more precisely identify patients who are or are not likely to benefit from adjuvant therapy, and individual host and treatment factors that influence the development of second cancer.