Many critically ill patients now survive what were previously fatal illnesses, but long-term mortality after critical illness remains high. While study populations vary by country, age, intervention, or specific diagnosis, investigations demonstrate that the majority of additional deaths occur in the first 6 to 12 months after hospital discharge. Patients with diagnoses of cancer, respiratory failure, and neurological disorders leading to the need for intensive care have the highest long-term mortality, while those with trauma and cardiovascular diseases have much lower long-term mortality. Use of mechanical ventilation, older age, and a need for care in a facility after the acute hospitalization are associated with particularly high 1-year mortality among survivors of critical illnesses. Due to challenges of follow-up, less is known about causes of delayed mortality following critical illness. Longitudinal studies of survivors of pneumonia, stroke, and patients who require prolonged mechanical ventilation suggest that most debilitated survivors die from recurrent infections and sepsis. Potential biologic mechanisms for increased risk of death after a critical illness include sepsis-induced immunoparalysis, intensive care unit-acquired weakness, neuroendocrine changes, poor nutrition, and genetic variance. Studies are needed to fully understand how the severity of the acute critical illness interacts with comorbid disease, pre-illness disability, and pre-existing and acquired frailty to affect long-term mortality. Such studies will be fundamental to improve targeting of rehabilitative, therapeutic, and palliative interventions to improve both survival and quality of life after critical illness.