It is time, we are told, to rethink epidemiology. It is time to rethink our quest, our concepts, and the nature and origin of our commitments. That is a lot of thinking, stretching across the broad landscape of our professional practice. Even our metaphors—this blind quest for the Philosopher’s Stone 1 — should be rethought, as well as our concept of cause, our much-maligned criteria of causation, our signature methods, and, it seems, our philosophical foundations. It is time, we are told, to step away from all that is associated with the natural laboratory of observational science, once the source of so many successes but now fraught with ‘profound and fundamental problems’, to use the precise language of Drs Buchanan, Weiss, and Fullerton. This is no ordinary rethinking. We need innovative, creative, out-of-the-box thinking, for we have been, to borrow a few familiar phrases, barking up the wrong tree, beating a dead horse, dreaming an impossible dream. It has been 5 years since the human genome was mapped. Long enough, it seems to Drs Buchanan, Weiss, and Fullerton, to determine that epidemiology cannot fulfil the promises that were made: the improvements in diagnosis, prevention, and therapeutics and a new kind of medicine that focuses on the ‘very essence’ of individual lives, guiding each of us along our unique trajectory, predicting precise risks for each and every one of us. 2 Epidemiology, we are told, cannot even provide society with the kind of knowledge science itself expects: consistent, reproducible results about the causes of all kinds of important concerns, such as cancer, heart disease, stomach ulcers, colds, autism, schizophrenia, syphilis, health care costs, healthier Americans, even aging, and, in the words of Drs Buchanan, Weiss, and Fullerton, ‘you name it’ when it comes to the causal effects of genes. Apparently, epidemiology was once a legitimate science of disease causation, but no longer. Who has not heard that we have found all the strong associations, with only the weak left to be discovered? To these dubious assertions about the past and not-yet-tested prognostications of the future, Drs Buchanan, Weiss, and Fullerton add a particularly chilling condition: even very large cohorts like those proposed for the Human Genome Project and by the investigators developing all those ‘biobanks’, cannot help the situation. 3 The underlying structure of biology connecting genes to individual traits—the ‘hour glass’ with gravity-defying grains of sand—prevents us from understanding anything new about weak biological effects using epidemiological studies. Small wonder we must rethink epidemiology, trying to understand how things could have gone so wrong in a present that is exploding in our faces. Let us begin by rethinking our quest: the metaphorical search for the Philosopher’s Stone.