To date, there are still a variety of human infections with unknown etiology. Identification of previously unrecognized viral agents in patient samples is of great medical interest but remains a major technical challenge. Acute respiratory tract infections are responsible for considerable morbidity and mortality in humans and animals. A variety of viruses, bacteria and fungi are associated with respiratory tract illness. Most of the respiratory viruses belong to the Paramyxoviridae, Orthomyxoviridae, Picornaviridae, Adenoviridae and Coronaviridae families. No pathogens can be detected in a relatively large proportion of patients with respiratory disease, partially owing to limitations of current diagnostic assays but also since some infections are caused by as yet unknown pathogens. This review will focus on human coronaviruses. In the mid 1960s, two human coronaviruses were identified that cause the common cold: human coronaviruses (HCoV)-229E and HCoV-OC43. The recent outbreak of severe acute respiratory syndrome-CoV and subsequent identification of two additional human coronaviruses (HCoV-NL63 and HCoV-HKU1) has drawn attention to this virus family. This review summarizes the knowledge of current methodologies for identifying novel human coronavirus species. Furthermore, information on the discovery of known human coronaviruses will be presented.