The presence of autoantibodies, particularly rheumatoid factors (RFs) and anticitrullinated protein antibodies (ACPA), is a hallmark of rheumatoid arthritis (RA). Recent studies have provided new insights into the biology, immunogenetics, and clinical relevance of these autoantibodies. RFs from RA patients target specific epitopes, and the determination of immunoglobulin A (IgA) isotypes of RF and ACPA can provide prognostic information, as their presence is associated with reduced therapeutic responses to TNF inhibitors. IgA levels are elevated in RA patients, and IgA immune complexes are more potent than IgG complexes in inducing neutrophil extracellular trap formation. AMPAs, including ACPA, also exhibit variable domain glycosylation (VDG), which affects antigen binding and autoreactive B cell activation. ACPAs have both pro-inflammatory and anti-inflammatory roles, contributing to joint destruction and pain perception while also showing protective effects in some contexts. The autoimmune response in RA is complex, and antibodies play crucial roles in its pathophysiology. The presence of IgA autoantibodies suggests a pivotal role in the inflammatory and destructive processes of RA, supporting the mucosal origin hypothesis. Seronegative RA remains a challenge, but recent studies suggest that a subset of these patients may harbor autoantibodies targeting modified or native proteins, allowing for further stratification. Overall, these findings enhance our understanding of RA and open new avenues for diagnosis, prognosis, and intervention.The presence of autoantibodies, particularly rheumatoid factors (RFs) and anticitrullinated protein antibodies (ACPA), is a hallmark of rheumatoid arthritis (RA). Recent studies have provided new insights into the biology, immunogenetics, and clinical relevance of these autoantibodies. RFs from RA patients target specific epitopes, and the determination of immunoglobulin A (IgA) isotypes of RF and ACPA can provide prognostic information, as their presence is associated with reduced therapeutic responses to TNF inhibitors. IgA levels are elevated in RA patients, and IgA immune complexes are more potent than IgG complexes in inducing neutrophil extracellular trap formation. AMPAs, including ACPA, also exhibit variable domain glycosylation (VDG), which affects antigen binding and autoreactive B cell activation. ACPAs have both pro-inflammatory and anti-inflammatory roles, contributing to joint destruction and pain perception while also showing protective effects in some contexts. The autoimmune response in RA is complex, and antibodies play crucial roles in its pathophysiology. The presence of IgA autoantibodies suggests a pivotal role in the inflammatory and destructive processes of RA, supporting the mucosal origin hypothesis. Seronegative RA remains a challenge, but recent studies suggest that a subset of these patients may harbor autoantibodies targeting modified or native proteins, allowing for further stratification. Overall, these findings enhance our understanding of RA and open new avenues for diagnosis, prognosis, and intervention.