OBJECTIVE The burden of severe and disabling neurologic injury on survivors, families, and society can be profound. Neurologic outcome prediction, or neuroprognostication, is a complex undertaking with many important ramifications. It allows patients with good prognoses to be supported aggressively, survive, and recover; conversely, it avoids inappropriate prolonged and costly care in those with devastating injuries. RESULTS Striving to maintain a high prediction performance during prognostic assessments encompasses acknowledging the shortcomings of this task and the challenges created by advances in medicine, which constantly shift the natural history of neurologic conditions. Embracing the unknowns of outcome prediction and the boundaries of knowledge surrounding neurologic recovery and plasticity is a necessary step toward refining neuroprognostication practices and improving the accuracy of prognostic impressions. The pillars of modern neuroprognostication include comprehensive characterization of neurologic injury burden (primary and secondary injuries), gauging cerebral resilience and estimated neurologic reserve, and tying it all together with individual values surrounding the acceptable extent of disability and the difficulties of an arduous convalescence journey. CONCLUSIONS Comprehensive multimodal frameworks of neuroprognostication using different prognostic tools to portray the burden of neurologic injury coupled with the characterization of individual values and the degree of cerebral reserve and resilience are the cornerstone of modern outcome prediction.