Disease modifying strategies are available for treatment of rheumatoid arthritis (RA), and good response rates are achieved. However, limitations include toxicity, including infectious complications in developing countries, a response rate ceiling, cost and rationing of biologic therapies, inability to cure or permanently reverse RA pathology, and inability to prevent disease. Immunotherapies targeting checkpoint molecules are markedly changing the landscape of clinical oncology. In autoimmune diseases such as RA, dendritic cells represent an important target for antigen-specific immunotherapy for T cell tolerance. Antigen-specific strategies promise greater specificity and safety, without general immune suppression, and thus the potential for intervention in at-risk subjects before disease onset. In a proof-of-concept trial, delivery of autoantigenic peptides and autologous tolerogenic dendritic cells was safe and had immunomodulatory effects on T cells including reduction of effector T cells and a relative increase in regulatory T cells. We have developed and are trialling in RA patients, antigen-specific immunotherapy targeting dendritic cells in situ with liposomes encapsulating autoantigenic peptide and calcitriol with the aim of antigen-specific T cell tolerance. I will discuss the development and future potential of antigen-specific tolerance strategies and the development of immune monitoring in clinical trials in RA and other autoimmune rheumatic diseases.