Children and adolescents with epilepsy are at increased risk for poor health-related quality of life (HRQL) even in the absence of active seizures. Clinicians who aim to achieve optimal seizure control also need to focus on improving HRQL. This can only be accomplished by recognizing how different features of the epilepsy itself, co-morbid conditions, as well as psychosocial factors can all make a difference to HRQL. These psychosocial factors include child, family and community/society variables that play a role in the well-being of these children. Conceptual models are relevant insofar as they provide us with a basis for hypothesizing the causal processes that lead to improved HRQL. They delineate what is meant by HRQL and highlight factors relevant to this important outcome. Researchers can use such models to test statistically and clinically relevant relationships. Clinicians can use this knowledge to direct the planning and implementation of services that are informed by these relationships, critically evaluate and then choose HRQL measures for use in clinical practice that most closely approximate what they understand HRQL is. The purpose of this review is to identify what is meant by HRQL as well as outline the theoretical and empirical basis for what it is about epilepsy, co-morbidity, and its treatment that we believe make a difference to HRQL.