Autoimmune chronic rheumatic inflammatory diseases are polygenic illnesses in which the inflammatory process mainly occurs in the synovial tissue, surrounding the joints. Dozens of inflammatory genes are upregulated or downregulated in each rheumatic disease. The genes of several of the molecules synthesized are often polymorphic and some of these polymorphisms have clearly been shown to be functionally relevant. In recent years monoclonal antibodies directed against some of the molecular targets have been developed, the first ones being the monoclonals against a key driver of synovial inflammation namely tumor necrosis factorα, followed by interleukin 1β, then interleukin 6 receptor and others. According to the background, the clinical benefits could be either partially driven by the pathobiological milieu, or by the polymorphisms of the genes encoding the target molecules. In this article the complex heterogeneity of the inflammatory genes regulating key molecules, which are targets of the therapeutic intervention with specific monoclonal antibodies is reviewed, along with the crucial data that could be obtained also on the inflammatory process by the ongoing clinical trials in which pharmacogenetics is mandatory.