Oral, small-molecule signalling pathway inhibitors, including ones that inhibit the JAK and other pathways, are currently in development for the treatment of rheumatoid arthritis (RA). Many of the pro-inflammatory cytokines implicated in the pathogenesis of RA utilize cell signalling that involves the JAK-STAT pathways and therefore inhibition of JAK-STAT signalling, by targeting multiple RA-associated cytokine pathways, has the potential to simultaneously reduce inflammation, cellular activation, and proliferation of key immune cells. Spleen tyrosine kinase (SyK) is a cytoplasmic tyrosine kinase that is an important mediator of immunoreceptor signalling in mast cells, macrophages, neutrophils, and B cells. Interruption of SyK signalling should interrupt production of tumour necrosis factor (TNF) and metalloproteinase and therefore affect RA disease activity. Tofacitinib, approved in many countries for the treatment of RA, is an orally administered small-molecule inhibitor that targets the intracellular Janus kinase 3 and 1 (JAK1/3) molecules to a greater extent than JAK2; there are other JAK inhibitors in development which are purported to be more specific for JAK3 (Vertex 509), specific for JAK1/2 (baricitinib) or more specific for JAK1 (Galapagos and INCYTE) where clinical data has been reported. Tofacitinib has been investigated in multiple clinical trials which have investigated its efficacy (clinical, functional, and radiographic) and safety in patients who have failed disease-modifying anti-inflammatory drugs (DMARDs) as monotherapy or in combination with DMARDs, compared to an inhibitor of tumour necrosis factor alpha (TNFα‎‎) and in patients who have failed TNFα‎‎ inhibitors. Vertex 509 has been investigated as monotherapy or in combination with MTX in DMARD failures while baricitinib, GLPG0634 (Galapagos), and INCB039110 (Incyte) have been investigated in phase 1 and 2 clinical trials in combination with MTX. Each of these medications has demonstrated efficacy; their safety profile has been shown to be generally similar although with some differences from each other and some differences from most of the currently approved biological agents. Fostamatinib disodium is an orally available inhibitor of SyK which was investigated in multiple phase 3 clinical trials in RA but was found to be generally ineffective with significant safety signals. This chapter discusses what is currently known and understood about the efficacy and safety of these oral, small-molecule DMARDs.