Historically, body tissues with a high rate of cell turnover, such as the bone marrow, have been most susceptible to chemotherapy-induced damage. The widespread use of hematopoietic colony-stimulating factors, as well as the development of new agents, has led to improved outcomes in many types of cancer. As a consequence, neurotoxicity has become increasingly important as a cause of dose-limiting chemotherapy toxicity. An understanding of the neurologic complications of these new agents is crucial in order to prevent irreversible neurologic injury. Moreover, chemotherapy complications that require discontinuation of a potentially effective drug need to be distinguished from other causes of neurotoxicity including the tumor itself, paraneoplasia, radiation and surgery, which may require a different therapeutic strategy. We review the prevalence, prevention, and management of important and unusual neurotoxicities related to chemotherapy and targeted agents approved by the FDA since January 1999. These agents include DNA-damaging agents such as oxaliplatin and temozolomide, microtubule poisons like ixabepilone, proteasome inhibitors (bortezomib), and signal transduction inhibitors such as imatinib, sunitinib and bevacizumab.