Cognitive side effects of systemic chemotherapy have become an increasing concern among breast cancer survivors, their families, and health care professionals. A growing body of research supports the hypothesis that chemotherapy can produce long-term cognitive changes in at least a subgroup of cancer survivors. We review evidence implicating systemic chemotherapy as the cause of cognitive changes; describe the limitations due to lack of longitudinal studies and gaps in knowledge (ie, no clear mechanism by which chemotherapy can produce cognitive changes has been proposed); discuss possible factors like age, intelligence quotient/education, and psychological, genetic, and hormonal factors that might increase risk for chemotherapy-induced cognitive changes; and outline future directions for research. Such future research includes large-scale, longitudinal studies of pretreatment neuropsychological assessments, use of imaging techniques and the development of animal models to study the mechanisms of chemotherapy-induced changes in cognitive functioning, and the development of interventions to prevent or reduce the negative cognitive effects of chemotherapy