Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by destructive hyperplasia of the synovium. Fibroblast‐like synoviocytes (FLS) are a major component of synovial pannus and actively participate in the pathologic progression of RA. How rheumatoid FLS acquire and sustain such a uniquely aggressive phenotype remains poorly understood. We describe the current state of knowledge of the molecular alterations in rheumatoid FLS at the genomic, epigenomic, transcriptomic, proteomic, and metabolomic levels, which offers a means to reconstruct the pathways leading to rheumatoid pannus. Such data provide new pathologic insight and suggest means to more sensitively assess disease activity and response to therapy, as well as support new avenues for therapeutic development.