Is the search for the causes of complex disease akin to the alchemist's vain quest for the Philosopher's Stone? Complex chronic diseases have tremendous public health impact in the industrialized world. Much effort has been expended on research into their causes, with the aim of predicting who will be affected or preventing effects before they arise, but progress has been halting at best. In this paper, we discuss possible reasons including the use of models and methods that fit point-source and Mendelian diseases but may not be as appropriate for complex diseases, reliance on causal criteria that may not be as relevant as they are for communicable diseases, and the biology of complex disease itself. Finally, we ask whether most complex diseases are even good candidates for the kind of prediction and prevention that we have come to expect based on experience with infectious and Mendelian disease.