Granuloma is an organized aggregate of immune cells that under the microscope appear as epithelioid macrophages. A granuloma can only be diagnosed when a pathologist observes this type of inflammation under the microscope. If a foreign body or a parasite is not observed inside the granuloma, stains for acid-fast bacilli and fungi are ordered since mycobacteria and fungi are frequently the cause of this type of inflammation. It is calculated that 12 to 36% of granulomas do not have a specific etiology and many have wondered if with new molecular methods we could reduce this number. This paper will summarize the frequently known causes of granulomas and will present the recent literature regarding the use of molecular techniques on tissue specimens and how these have helped in defining causative agents. We will also briefly describe new research regarding formation and function of granulomas and how this impacts our ability to find an etiologic agent.