Proper therapy for infectious disease requires knowledge of the etiologic agent. This knowledge can be gained in two ways: directly, either by isolating and identifying the organism in culture or by some method (e.g., fluorescent antibody or nucleic acid probe) that permits specific visual detection of the organism in clinical material; or indirectly, by using serologic tests that demonstrate antibodies against an organism in the patient’s blood. Certain problems arise in the interpretation of direct methods or serologic test results. If results of the direct method are positive, one must determine whether the organism reported has clinical significance. It may be a fortuitous contaminant, an ordinarily nonpathogenic species that has become infectious under the prevailing circumstances, or a recognized pathogen that is a normal inhabitant of the area and whose presence may be entirely harmless. If results of the direct method are negative, one must consider the possibility of having missed the diagnosis because the laboratory was not given a proper specimen, because the specimen was obtained at an unfavorable moment during the disease, or because of laboratory technical problems (and, if culture is involved, because special culture techniques or media might have been needed). Serologic tests that detect antibodies also have drawbacks in bacterial diseases, since it takes 7-10 days after infection (sometimes longer) to develop detectable antibodies, and it is often necessary to demonstrate either a very high titer or a fourfold rising titer of antibodies to differentiate recent from old infection. Therefore, to evaluate laboratory data, the clinical situation has at least as much importance as laboratory methodology. It seems desirable to provide a brief survey of the major infectious agents, the diseases and circumstances in which they are most often found, and the conditions under which the appearance of these organisms may be confusing. There is an element of classification because of the way laboratory reports are usually worded. Techniques of diagnosis in the area of infectious disease are discussed in this chapter in relation to specific organisms, specific clinical situations, or general laboratory methods.