When discussing the benefits and burdens of medical interventions for critically ill infants, clinicians and families are challenged to weigh the uncertainties of treatment success with infant pain and suffering. Concrete measures of infant suffering or quality of life, which could inform infant care and decision-making are lacking. Although consistent and reliable health-related quality of life (HRQOL) definitions and measures have been extensively developed for adults and older children, they have not been relevant to neonates or infants. Advancing HRQOL research methodology is an objective of Healthy People 2020. This paper will review the evidence and practices relevant to HRQOL with a focus on intensive care and pediatric settings. We will highlight existing HRQOL measures, which could be adapted for neonates and existing neonatal intensive care unit measures and practices, which could inform new measures of HRQOL.