The search for cerebral markers is of great interest, but lacking a detailed theory of how psychopathology relates to cerebral dysfunction, we must recognize that this is useful, rather than definitive, exploratory work. Unfortunately, the history of biological psychiatry is replete with reports of baseline differences between patients and normal subjects that turn out to be artifacts, since these are naturalistic, multiply confounded, rather than experimental, studies. I believe the differences between patients and normal comparison subjects that have stood up best have been the outcome of challenge studies, e.g., lactate infusion, sedation threshold, CO2 inhalation. Much psychopathology may be due to adaptive deficiencies in cybernetic control mechanisms, best revealed by perturbing the system rather than simply observing it at rest. Combining challenges with genetic studies may prove a useful strategy in dealing with the multiple phenocopy problem.