Historical and most currently held views of microbial pathogenesis and virulence are plagued by confusing and imprecise terminology and definitions that require revision and exceptions to accommodate new basic science and clinical information about microbes and infectious diseases. These views are also inherently unable to account for the ability of some microbes to cause disease in certain, but not other hosts, because they are grounded in singular, either microbe-or host-centric views. The damage-response framework is an integrated theory of microbial pathogenesis that puts forth the view that microbial pathogenesis reflects the outcome of an interaction between a host and a microbe, with each entiry contributing to the nature of the outcome, which in turn depends on the amount of host damage that results from the host-microbe interaction. This view is able to accommodate new information and explain why infection with the same microbe can have different outcomes in different hosts. This chapter describes the origins and conceptual underpinnings of and the outcomes of infection put forth in, the damage-response framework.