This paper discusses a series of important methodological issues in developing targeted health-related quality of life measures in studies of the effects of medical interventions. Such measures cannot be developed unless the evaluator understands the life domains that medical interventions affect. Qualitative discovery methods are needed to obtain this understanding. Once domains are targeted for measurement, careful and systematic laboratory pilot work should be used to select initial scale items. Psychometric evaluation of response patterns in subsequent field tests is needed to assess the measures. Less concern should be directed to internal consistency reliability of scales in the psychometric evaluation and more to the ability of short scales to reproduce total scale variance and to provide precise measurement within the range of the outcome where effects are expected. The paper closes with a discussion of modern methods of item response scaling that can be used to address these issues.