In requesting that I prepare a concluding essay for New Knowledge in the Biomedical Sciences, the editors assigned me the title "The End of the Era of Optimism!" indicating, or so I presumed, that the papers being presented required tempering with the heat of realism. Having reviewed the manuscripts making up this volume, I have concluded that their authors are well aware of the crises facing medicine today, and are little in need of having their attention drawn to the limitations of a too optimistic view of their disciplines. I have therefore taken as my tasks an analysis of their reasons for believing that the current history of the acquisition and use of biomedical knowledge has reached a period that might be described as pessimistic, and, in a limited way, a presentation of some modest reasons for maintaining that a modicum of optimism is nevertheless in order.