The Henle-Koch postulates are reviewed in terms of their full validity in Koch's day and in light of subsequent developments. The changing guidelines developed for viral diseases, for viruses in relation to cancer and to chronic central nervous system infection, and for causative agents in chronic diseases are discussed chronologically. A set of guidelines for both acute infectious and chronic diseases is presented. The need for recognizing the role of the host and the spectrum of host responses, for sound biologic sense in evaluating causal roles of agents in disease, and for flexibility in adapting our guidelines to new knowledge are emphasized.