As a result of an increased demand for international cooperation in health care, cross-cultural quality of life (QOL) measures have been developed and tested. At present, a considerable number of QOL instruments are available in various languages, and some have been validated and normed in specific countries. Different approaches highlighting specific tasks have been used, and standards and guidelines for cross-cultural development and testing are now available. However, specific populations, such as persons with disabilities or chronic health conditions as well as minorities, have been neglected in international research. This article presents the current issues confronting cross-cultural instrument development in QOL. It describes the steps of international QOL instrument development and highlights some of the challenges, referring in particular to an ongoing project devoted to children with disabilities and chronic conditions.