Fibroblast-like synoviocytes (FLSs) are important non-immune cells located mostly in the inner layer of the synovium. Indeed, these cells are specialized mesenchymal cells, implicated in collagen homeostasis of the articular joint and provide extracellular matrix (ECM) materials for cartilage and contribute to joint destruction via multiple mechanisms. RA FLS interactions with immune and non-immune cells lead to the development and organization of tertiary structures such as ectopic lymphoid-like structures (ELSs), tertiary lymphoid organs (TLOs), and secretion of proinflammatory cytokines. The interaction of RA FLS cells with immune and non-immune cells leads to stimulation and activation of effector immune cells. Pathological role of RA FLS cells has been reported for many years, while molecular and cellular mechanisms are not completely understood yet. In this review, we tried to summarize the latest findings about the role of FLS cells in ELS formation, joint destruction, interactions with immune and non-immune cells, as well as potential therapeutic options in rheumatoid arthritis (RA) treatment. Our study revealed data about interactions between RA FLS and immune/non-immune cells as well as the role of RA FLS cells in joint damage, ELS formation, and neoangiogenesis, which provide useful information for developing new approaches for RA treatment.