Over the past decade, there has been significant progress made into the field of quality of life in cancer clinical trials. Many cancer clinical trials now include quality of life as a secondary end-point, but only a very small number of trials include quality of life as a primary end-point. This article reviews and discusses issues that arise when developing a quality of life instrument for use in international cancer clinical trials. We describe problems that arise when trying to establish item equivalence across cultures that the instrument development team should be aware of. We also outline approaches in the literature to establish item equivalence across different cultural groups both in a linguistic and conceptual manner. Finally, statistical and psychometric approaches to assess cultural differences and cultural equivalency that have appeared recently in the literature are described and reviewed.