Quality of life (QoL) refers to an individual's sense of overall well-being encompassing physical, psychological, emotional, social, and spiritual dimensions. Although genetics healthcare providers strive to promote patient well-being, and the term QoL is often invoked to refer to this outcome, there is lack of clarity as to what actually constitutes QoL from the patient's perspective. This systematic literature review aims to summarize and integrate research findings to help elucidate how healthcare providers can more effectively enhance the QoL of patients affected with rare genetic conditions. Eligible studies were those that measured QoL as a primary outcome variable using a validated, multi-dimensional scale. Detailed criteria were used to rate quality of design, methodology, and analytic rigor. Fifty-eight studies were selected for inclusion in the review, and a narrative synthesis of the data was performed. A central theme emerging from the literature is that, although genetic conditions have the potential to have significant negative consequences for individuals' lives, having a genetic condition does not necessarily entail poor QoL. Evidence demonstrates that factors beyond the physical manifestations of the disease, such as psychological well-being, coping, and illness perceptions, influence QoL and may serve as potent targets for intervention. The field of research on QoL in rare genetic conditions will be advanced by uniting around a clear conceptualization of QoL and using more rigorous methodology with comprehensive measures of global QoL.