The distribution and diversity of microorganisms in the world are far greater than have been previously appreciated. Molecular, cultivation-independent methods have played a key role in this insight. To what extent do humans remain ignorant of microbial diversity within the human body and the settings in which microorganisms cause human disease? In addition to implicating microbial agents in nontraditional infectious diseases, the use of methods such as broad-range polymerase chain reaction, representational difference analysis, expression library screening, and host gene expression profiling may force a reassessment of the concepts of microbial disease causation.