In spite of rather negative publicity on the crossover/self-controlled design for clinical trials in the early 1980s, a fair number of these studies were published in that period. Using these studies as examples, we try to give an overview of major advantages and disadvantages of crossover and parallel group studies. Strengths of the crossover versus the parallel design include: (1) elimination of between-subject variability of symptoms; (2) no need for large samples; (3) fewer ethical problems; and (4) subjects are able to express their preference for one of the compounds being given. Weaknesses include: (1) carryover effect from one treatment period into the other; and (2) time effect due to spontaneously evolving symptoms in a lengthy trial. Although routinely used for all types of therapies in phase I/II studies, the crossover/self-controlled design cannot be used in phase III/IV studies other than for symptomatic treatments of stable disease. Treatments of chronic diseases are directed primarily to the relief of persistent symptoms rather than the cure of a rapidly evolving symptomatology. These very aspects make them particularly suitable for crossover/self-controlled studies. Awareness of the weaknesses of clinical trials is especially important to clinical practitioners, who depend on reported clinical trials when making clinical decisions.