Anti-citrullinated protein antibodies (ACPAs) of the IgG subtype have become a critical hallmark of HLA-associated rheumatoid arthritis (RA) and point to important contributions from the adaptive immune system. To dissect the contributing autoimmune reactions, investigators must not only identify the protein targets of ACPA but also define the precise peptides recognized by the immune system. Several possible approaches could be used to achieve this goal, and sensitive mass spectrometry of relevant tissue is a promising way forward in advancing our detailed understanding of autoimmune immune reactions involved in RA pathogenesis.