Rheumatoid Arthritis (RA) is a common autoimmune disease that causes chronic inflammation of the tissues around the joints, which eventually results in systemic complications and bone destruction. Macrophages are critical cells in many tissues and organs essential to an innate and adaptive immune response. It is one of the most common cell types in the synovium of rheumatoid arthritis. Various conventional and experimental therapies for RA target proteins, cytokines or their synthetic pathways, T lymphocytes, and B lymphocytes. The Fibroblast-Like Synoviocytes (FLS) and macrophages are abundantly activated in RA, and the drugs targeting the monocytes and macrophages are explored significantly less. The drugs targeting monocytes and macrophages may provide a better therapeutic strategy for RA. Proteasome inhibitors act as a potential remedy for autoimmune and inflammatory diseases. Targeting the monocytes and macrophages with proteasome inhibitors may improve the therapeutic approaches to RA. This paper reviews the types and significance of macrophages in RA, various conventional and experimental therapy approaches targeting monocytes and macrophages, and the effect of proteasome inhibitors on macrophages in RA.