Rheumatoid arthritis (RA) is a common, but heterogeneous, disease. Usually, when it comes to the pathogenesis of RA the physician faces a complex network of cytokines and cells of the immune system—the so-called effector level. However, is this network ‘the cause’ of the disease? Or is this rather the level most physicians are somewhat familiar with, as modern anti-rheumatic medications are having their targets there? In this review, we are looking beyond the usual culprits from the physician’s perspective and discuss how other factors, such as genes, epigenetics, environmental factors, local joint characteristics or processes of aging might influence the clinical phenomenon RA.