The intestinal epithelium represents an exquisite complex combination of specialized cellular components, structural organization, as well as fine-tuned maintenance and renewal mechanisms that ensure its barrier and absorptive function. Defects in one or more of these components can lead to devastating consequences for the organisms, and when chronic, even develop into inflammatory diseases, such as Crohn's disease or ulcerative colitis. In these scenarios, the cytokine TNF (Tumor Necrosis Factor α) appears to be a major inflammation-promoting and tissue damage-promoting effector molecule. Besides its role in inflammation and cell death, TNF presents a wide range of pleiotropic activities with implications in various cellular processes, including proliferation and differentiation. Moreover, more recent evidences suggest an anti-inflammatory role of TNF, mostly via the induction of local glucocorticoids synthesis in the intestinal epithelium. Thus, the outcome of TNF receptor signaling largely depends on various factors, like the TNFR composition and the precise cellular context or tissue type, which will determine the cellular fate. In this review, we discuss the molecular mechanisms and their potential crosstalk that regulate the different TNF-initiated cellular outcomes in the intestine, as well as possible applications for pharmacological interventions in the treatment of inflammatory disorders of the intestinal mucosa.