Many cancer patients develop treatment-related cognitive dysfunction that affects their quality of life and can result in diminished functional independence. There is an emerging body of transdisciplinary research demonstrating that chemotherapeutic agents can produce neurobiological changes within the brain, which are associated with a constellation of cognitive changes that can result in decreased quality of life and functional independence. The increased incidence of cancer, coupled with longer survival times, has resulted in larger numbers of cancer survivors who are struggling with this neurotoxicity. This review summarizes the neuropsychological findings in patients with breast and brain cancer who receive systemic chemotherapy as well as the recent animal and imaging research elucidating the mechanisms by which these therapies impact brain structure, function, and consequent behavior.