The network of cytokines, released by resident and migrating cells (lymphocytes and phagocytes), involved in periodontal bone resorption. Resident cells including epithelial cells (ECs), gingival fibroblast (GFs), periodontal ligament fibroblasts (PDLFs), osteoblast, and dendritic cells mediate the Innate Immunity. They respond to the bacterial challenge (via TLRs) by producing proinflammatory cytokines and chemokines. ECs produce IL-8, a neutrophil chemoattractant, which recruits neutrophils (neu) and increases monocyte (mono) adhesion. Neu in turn produces IL-1, IL-6, and TNF-, while Mono can differentiate into osteoclasts (OCs). DCs produce IL-12 and IL-18 but also act as antigen-presenting cells for B and T Cells. GFs produce IL-8, TNF-, and IL-6. PDLFs produce IL-1, IL-6, TNF-, and RANKL. Microorganisms can go deeper in the periodontal tissue and reach the surface of alveolar bone, promoting the expression of the proosteoclastogenic cytokine RANKL by osteoblasts (OBs). These inflammatory cytokines are directly (as RANK-L and TNF-) or indirectly involved in osteoclastogenesis and are responsible for the alveolar bone loss. After this initial response (lasting approximately 21 days), activation of T and B cells by antigen-presenting cells initiates the adaptive immunity. As a result, tissues affected by periodontitis become colonized with both lymphocyte subtypes, but with a larger proportion of B cells than T cells. The majority of B cells in periodontal lesions are RANKL+. T cells produce the proosteoclastogenic cytokines RANKL and TNF-, and IL-17 which exerts its osteoclastogenic activity by enhancing RANKL expression on osteoblasts. Furthermore a new role for TRAIL, produced in periodontitis, is emerging in promoting osteoclastogenesis and favoring OBs apoptosis.