Distal colitis refractory to standard therapy is a complex and challenging problem. Physiological differences between the right and left colon may be exploited for maximum therapeutic benefit. Overreliance on oral therapy should be seen as one of the reasons for treatment failure and delivery systems should target therapy to the distribution of the disease in doses proven to be therapeutically beneficial. The clinician should also be cognizant of potential adverse effects of standard therapies, particularly colitis due to mesalazine, which may mimic worsening disease. Numerous endogenous and exogenous factors that may exacerbate the underlying inflammatory bowel disease are discussed. This review explores the potential mechanisms why distal colitis may be refractory to therapy and addresses newer therapies that, while still in the investigatory stages, offer hope for a widening armamentarium of therapeutic modalities.