Successful treatment of many childhood diseases once considered terminal has resulted in the emergence of long-term effects of the disease or consequences of treatment that were previously unrecognized. Many of these long-term effects involve the central nervous system (CNS) and are developmental in the way that they emerge over time. Because we are now able to observe the natural history of childhood diseases such as sickle cell anemia or HIV, or the consequences of treatment of disease such as leukemia, brain tumors, or kidney disease, we are also able to study a number of biological mechanisms that result in long-term neurocognitive impairment. While some of the neurodevelopmental outcomes can be directly linked to structural damage of the CNS, other systems (e.g., hematologic, immunologic, pulmonary) appear to play crucial indirect roles in the development of the CNS and neurocognitive abilities because of the way that they affect the course of brain development and activity of the brain across time. Important interactions between acute disease factors, biological mechanisms, age at the time of disease or treatment effect, and disruptions in patterns of development after successful treatment or management all provide support for a neurodevelopmental model of childhood chronic illness. Testing this model may make it possible to more accurately predict the timing and degree of severity of long-term neurodevelopmental consequences, provide guidance for improved treatment and prevention, and offer better understanding of neurodevelopmental disruptions that occur in other non-chronic illness related disabilities.