Assessment of health related quality of life (HRQoL) has been addressed in medicine since more that 20 years. However, little is known about the HRQoL of patients with traumatic brain injury (TBI). The main reason for this seems to be the challenge of attempting to assess HRQoL in the light of the diversity of consequences associated with the condition. Especially in severely brain-damaged patients with altered states of consciousness, patients self-report on own function and well-being seems at least difficult, if not impossible, and the question is whether other persons, like caregivers, might be able to truly judge the patients quality of life. A prerequisite to examining HRQoL in patients with TBI is the availability of appropriate measures. While generic measures are available, the development of condition-specific measures has only recently begun. This chapter reviews conceptual and methodological issues in current HRQoL research, applies these to the area of brain injury and critically summarizes challenges to HRQoL assessment in TBI in terms of potentials and limitations. It is concluded that in spite of recent promising approaches to HRQoL assessment in TBI, much has to be done to understand, measure and finally improve HRQoL in severely brain-damaged patients.