Host defense against pathogenic microbes requires dramatically different responses, depending on the character of the pathogen and on the tissue under attack. Central to the immune system's ability to mobilize a response to an invading pathogen is its ability to distinguish self from nonself. The host has evolved both innate and adaptive mechanisms to respond to and eliminate pathogenic microbes. Both of these mechanisms include self-nonself discrimination. This overview describes key mechanisms used by the immune system to respond to invading microbes and identifies settings in which disturbed immune function exacerbates tissue injury.