Giant cell granulomas in the oral cavity are reactive hyperplastic lesions that arise either peripherally in the mucoperiosteum or centrally in the bone. The peripheral giant cell granuloma (PGCG) is a benign lesion induced by local chronic irritation. It may develop at any age, and tends to be more frequent in females. Central giant cell granuloma (CGCG) is a reactive lesion of unknown etiology. It commonly occurs in children and young adults. It is also predominant in females and frequently located in the anterior part of the mandible. Histologically, PGCG and CGCG have similar features. The lesions are non-encapsulated proliferations of oval and spindle-shaped mononuclear cells (MCs) and multiple multinucleated giant cells (MGCs) in a vascular supporting stromal tissue, associated with foci of hemorrhage. Despite the similar microscopic features, PGCG and CGCG have different clinical behavior. PGCG is usually reduced in size and asymptomatic. It grows locally, as an exophytic lesion on the alveolar mucosa, but may become slightly infiltrative in the underlying periosteum and bone. After complete excision and curettage, it has a low recurrence rate. Contrarily, CGCG has an aggressive behavior, with rapid growth and intense osteolytic activity causing perforation of the cortical plate, teeth malposition and pain. Moreover, it is characterized by a high recurrence rate. This review focuses on the origin and activating pathways of MCs and MGCs, discusses the mechanisms underlying their biological activity, tries to explain the variable clinical behavior and proposes therapeutic approaches for the granulomas associated with the jaw bones.