Rheumatoid arthritis is characterized by multiple pathobiological processes and heterogeneous clinical phenotypes. Not surprisingly, the inflamed synovium harbors an equally complex pathology. This includes variability in infiltrating and resident cell populations, spatial arrangements, and cell-cell interactions, as well as gene expression profiles. Remarkable progress in our understanding of the many facets of tissue heterogeneity has been facilitated by the increasing availability of patients' material and the development of advanced research technologies. The next challenge is to capitalize on the large amount of data generated to elucidate the specific pathogenic pathways disparately activated in different patients and/or different phases of the disease. When tissue pathology can be reliably explored through noninvasive circulating biomarkers, then the circle will be closed. We attempt to highlight key advances in the understanding of synovial tissue heterogeneity in rheumatoid arthritis and summarize novel perspectives in synovial biomarker discovery in relation to peripheral blood.