Since its initial description 125 years ago, sarcoidosis continues to be a "challenging" disease. Its etiology remains unknown. Discovering the etiology of sarcoidosis remains a major goal with important implications regarding treatment, predicting outcome, as well as determining approaches for preventive measures. Immunological responses and granulomatous tissue formation characterizing sarcoidosis are similar to those observed in a variety of infectious diseases. However, the nature of the specific antigen(s), which putatively trigger the inflammatory response in sarcoidosis, remains elusive. Occurrence of sarcoidosis in spatially related clusters, and household and health care settings strongly support person-to-person transmission of an infectious agent as one of the potential causes of this disease. Sarcoidosis has been associated with a variety of infectious agents, none of which can be cultured. Propionibacterium acnes (P. acnes) and M.tuberculosis (Mtb) are the most commonly identifiable infectious pathogens by PCR-based methods and considered to be associated with the development of this disease. Immunological studies in sarcoidosis have focused largely on the assessment of constitutive, immune responses and the description of the phenotypes of blood and lung cells in patients and control subjects.