The diagnosis of lymphoproliferative and granulomatous disorders can be very challenging given their heterogeneous morphological features and the large number of differential diagnoses and so the use of ancillary techniques is often required. Immunohistochemistry represents the most common technique used to investigate the immunophenotype of these lesions, and pathologists should be familiar with the main markers, some of which are also very important for targeted therapy and prognostic determination. The identification of EBV in tumor cells, again using immunohistochemistry, can aid diagnosis in many cases; however, in situ hybridization for the detection of EBV RNA (EBER) is more sensitive and thus a preferred tool. A better understanding of the molecular basis of lymphoproliferative disorders has led to the identification of numerous genetic events that carry pathogenetic and/or diagnostic importance, and their recognition through fluorescent in situ hybridization, PCR, or next-generation sequencing contributes to a better diagnosis and to a better understanding of the pathogenesis of these lesions. In this chapter, the main immunohistochemical markers, the methods used to investigate the presence of EBV, and the most important genetic events occurring in lymphoproliferative and granulomatous disorders in the oral cavity are described and discussed.