The main research questions concerning mood and chronic disease are about the extent, sources, and consequences of emotional distress. Answers to these questions are informative both to psychological theory and to the design of interventions aimed at improving outcomes for patients. However, as a result of practical and ethical limitations in research designs, the answers obtained are rarely definitive and typically need to be interpreted carefully. This article illustrates some of the problems using studies of patients with cancer, myocardial infarction, stroke, and other disabling conditions. The first group of studies illustrates problems in the timing of mood measurement including both timing within an interview, and issues concerned with identifying equivalent timing in the stages of disease and its treatment. The remaining studies are used to illustrate the limits of non-experimental longitudinal, and of experimental designs. It is concluded that research in this area requires the use of more than one research paradigm to achieve dependable answers.