Ulcerative colitis is a chronic inflammatory condition of the large intestine whose etiology remains largely unknown. Its pathogenesis involves the breakdown of intestinal mucosal homeostasis due to a genetically determined miscommunication between commensal flora and the gut associated immune system. Cytokines are central components of the inflammatory pathways that take place during the active and chronic phases of ulcerative colitis. Recent research has identified several novel cytokine systems that are upregulated at the mucosa of patients with ulcerative colitis and started to unveil their functional importance for disease pathogenesis. The significance of interleukin-13 (IL-13), TNF-like cytokine 1A (TL1A), IL-33, and their receptors in ulcerative colitis is strongly supported by converging expression and functional data. These molecular systems may define subgroups of patients with uniform immunological profiles. Within these subpopulations such novel cytokine systems may serve as markers of biological activity of the disease. More importantly, they may offer unique therapeutic opportunities through the development of drugs that specifically target and neutralize well-defined inflammatory pathways.