These quotes, from an article in Time magazine, sound themes repeated again and again by those who believe that the major causes of complex diseases are to be found in our genes. Justifications for continuing to pour taxpayer and investor money into the search for genetic causes of complex disease include: (1) that we stand at the threshold of great discovery, with major advances in health right around the corner as a consequence; (2) we are not doing this for ourselves, or even for our children, but for our children’s children; (3) although the odds are long on actually unravelling the causes of disease with current approaches, we might make an accidental discovery along the way; (4) science works incrementally and discoveries are made in fits and starts, and expecting quick results is asking too much (see number 1); (5) there have been notable successes and we risk missing others if we change course now; (6) science progresses as much by rejecting hypotheses as by confirming them, so the inconsistent results so common in complex disease research justify an ever expanded search effort; or (7) we do this because nothing else is working. These are some of the regularly offered justifications for current genetic epidemiological research, but they are matched by far fewer cautions. We appreciate the thought respondents gave to our paper. 1–7 We are well aware that we provided a large target, and are pleased that, for the most part, our cautions were not dismissed out of hand. Nor did the respondents gainsay our attempt to explain the epistemological reasons for the problems that we face today. We find it telling that even the respondents who question our views neither refute them specifically nor mount any kind of vigorous defence of the status quo beyond stating what essentially amounts to a belief that extending current methodology with ever larger, longer studies and more technological and biostatistical sophistication, and, of course, moving to genetics will do the trick. Indeed, several respondents sound even more dire warnings than our own. Some proffer solutions, but they generally do not take into account the changing biological landscape facing both epidemiology and human genetics now that ’easy’ diseases have been explained (responsible genes or environmental risk factors identified for essentially single cause diseases). All the respondents would no doubt agree with Dr Weed 2 , as we do, that epidemiology has a venerable history. Its practitioners surely share Dr Weed’s belief that ‘health is a fundamental social good’, and enhancing this social good is why most people are in this field and why we undertook to write the kind of paper we wrote: when a discipline faces fundamental problems, it does no one—particularly students—a service to deny them. When we have been feeding the public exuberant promises of enormous return on investment, from personalized medicine to near-immortality, it is wrong to evade accountability for how their investment is spent. And, arguably the stakes are higher now than they have ever been—many of the proposed fixes for complex diseases require greater resources, for potentially smaller returns, than ever before. As several respondents noted about our metaphor, alchemy was not entirely in vain. Indeed, it occupied leading scientific thinkers for centuries, including Isaac Newton himself. Some threads ultimately morphed into modern chemistry. But in this context one respondent objected to our raising the subject of vested personal and professional interests as an obstacle to progress—that we refer to as an ‘informal Bayesian’ effect on the way we make inferences—so it is entirely in order for us to note that alchemists were trying to turn base metals into gold, not oatmeal (and Newton finished his career in charge of the Royal Mint!). At least they were doing it largely with their own venture capital. Funding, institutional, and career dependencies are substantial inertial factors in many areas of science, including complex disease research. These things are widely acknowledged privately, but rarely publicly, for the obvious reason that public support is required for research and our society works by lobbying and public persuasion. It would be highly disingenuous to deny that funding availability has a major effect on research 1 Department of Anthropology, Penn State University, University Park, PA 16802, USA. 2 Department of Biology, Penn State University, University Park, PA 16802, USA. 3 Department of Medical History and Ethics, University of Washington School of Medicine, Seattle, WA 98195, USA.