The term "atypical" pneumonia has been used to differentiate infections caused by Chlamydia pneumoniae, Mycoplasma pneumoniae, Legionella, and other related organisms from pneumonia caused by classic bacteria, the prototype being Streptococcus pneumoniae. However, recent studies demonstrated that the clinical presentation of pneumonia due to atypical pathogens cannot readily be differentiated from those caused by "typical" bacteria. This is further complicated by the observation that coinfections with atypical pathogens and other bacteria are frequent. Nonetheless, the term "atypical" can be useful, as these organisms share a number of characteristics that separate them from "typical" bacteria. They are either obligate or facultative intracellular parasites that cannot be isolated using routine microbiologic methods. The most commonly used method of diagnosis of these infections is serology, which has significant limitations. Although C. pneumoniae is now recognized worldwide as a common cause of respiratory infections in adults and children, major gaps remain in our knowledge of the biology of this organism and how it causes disease, in major part due to the lack of readily available, standardized diagnostic methods.