<p>Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent synovial inflammation that leads to progressive cartilage breakdown, bone erosion, and functional impairment. Among the cytokines involved in this process, tumor necrosis factor alpha (TNF-α), primarily produced by activated macrophages and T lymphocytes, acts as a central regulator of inflammatory signaling. Through its effects on synovial fibroblasts and various stromal and immune cells, TNF-α enhances the production of tissue-damaging enzymes and inflammatory mediators while supporting inflammatory cell recruitment into the joint. Macrophages and dendritic cells (DCs) are critical immune populations that shape these pathogenic processes, with synovial macrophages generating pro-inflammatory cytokines that contribute to joint damage and DCs sustaining autoreactive immune responses through self-antigen presentation and autoreactive T-cell activation. The clinical effectiveness of TNF-α inhibitors highlights the central involvement of this pathway in RA pathogenesis, demonstrating their ability to reduce inflammatory activity, slow structural deterioration, and improve functional outcomes, partly through modulation of macrophage and DC behavior. This review synthesizes the current understanding of macrophage- and DC-mediated mechanisms in RA and examines how TNF-α signaling and targeted TNF blockade reprogram these cellular processes, highlighting the immunologic basis of RA and the rationale for TNF-α directed treatment strategies.</p>