In depth molecular and cellular analysis of synovial tissue and fluid from patients with rheumatoid arthritis has provided important insights into understanding disease pathogenesis. Advances in the 1980s and 1990s included modern cloning strategies, sensitive and specific assays for inflammatory mediators, production of high-affinity neutralizing monoclonal antibodies, advances in flow cytometry, and gene targeting and transgenic strategies in rodents. In the 21st century, technological platforms offer unparalleled opportunities for systematic and unbiased interrogation of the disease process at a whole-genome level. Here we describe the key molecular and cellular characteristics of the inflamed synovium and how infiltrating cells get there. With this background, we outline current concepts of the different phases of disease, how the first phase of genetic susceptibility evolves into autoimmunity, triggered by the exposome, prior to the onset of clinically apparent inflammatory disease. We then describe the pathways that actively contribute to this early inflammatory phase and document the key effector cells and molecules of the innate and adaptive immune systems that orchestrate and maintain chronic synovial inflammatory responses. We summarize how this inflammatory milieu translates to cartilage destruction and bone resorption in synovial joints, and conclude by reviewing those factors in inflamed synovium that promote immune homeostasis.