Injury to the intestinal epithelium can result in DNA damage and altered gene expression and function, the initial step required for neoplastic transformation. In addition, this is accompanied by activation of NF-κB within epithelial cells, which promotes prosurvival pathways that are required for the initial growth of the resulting neoplastic cells. NF-κB activation also promotes proinflammatory gene expression. TNF-α originating from the mucosa or possibly the epithelium itself, participates in orchestrating the activation of immune cells. Production of various proinflammatory factors by the activated immune system participates in the ensuing inflammatory response but additionally plays a role in tumor growth by providing trophic signals to the early neoplastic lesions. Loss of TNF-α signaling in immune cells, and not the mucosa, stops this cascade by aborting the mucosal inflammatory response, and this can be achieved by pharmacologic blockade of TNF-α with etanercept and possibly other agents (21).