Long-term neurotoxicity associated with central nervous system (CNS) prophylaxis for childhood acute lymphoblastic leukemia (ALL), primarily involving physical growth and cognitive development, is an ongoing concern. Although contemporary treatment protocols are associated with less severe toxicity than was commonly observed with earlier protocols, there continue to be late effects. When treatment includes cranial radiation therapy (CRT), linear growth is likely to be impaired. Female patients are more vulnerable to late cognitive effects than male patients, particularly when treated with CRT and high doses of methotrexate. Young age at treatment is a risk factor as well, particularly for girls. In order to treat medical and psychological problems early, a commitment to long-term follow-up is essential.