Many chronic inflammatory diseases are associated with deregulated intracellular signal transduction pathways. Resultant pathogenic interactions between immune and stromal cells lead to changes in cell activation, proliferation, migratory capacity, and cell survival that all contribute to inflammation. Increasing efforts are now being made in the design of novel therapeutic compounds to interfere with signaling pathways in inflammatory diseases like rheumatoid arthritis (RA). In this review we will outline the major signal transduction pathways involved in the pathogenesis of RA. We will assess advances in targeting a number of key intracellular pathways, including nuclear factor-(kappa)B (NF-(kappa)B), mitogen-associated protein kinases (MAPKs), phosphoinositide 3-kinase (PI3K)/Akt, signal transducers and activators of transcription (STATs), and reactive oxygen species (ROS) production. Finally, we will discuss recently identified lead molecules and the progress of selected compounds towards becoming new drugs for the treatment of inflammatory diseases.