Diseases of the orbit and periorbital eye tissues manifest in a wide variety of clinical presentations. Space-occupying lesions in the orbit include infections, inflammations, vascular malformations, and malignancies. The significant variation in presentations is due to the complex anatomy of the orbit and the heterogeneous nature of the multiple disease processes that present themselves as orbital inflammatory processes. This heterogeneity creates a significant challenge in determining specific diagnoses and subsequently instituting timely medical and surgical management of patients with orbital inflammation. Despite advances in imaging, physical examination, and laboratory tests, a biopsy is often needed for diagnosis and to guide treatment. Unfortunately, biopsy is too often read as nonspecific or idiopathic inflammation, a term that gives minimal guidance to the patient or to the clinician. There is clearly a need for developing more specific and sensitive clinical diagnostic testing.