The ability of epithelial cells to organize through cell-cell adhesion into a functioning epithelium serves the purpose of a tight epithelial protective barrier. Contacts between adjacent cells are made up of tight junctions (TJ), adherens junctions (AJ), and desmosomes with unique cellular functions and a complex molecular composition. These proteins mediate firm mechanical stability, serves as a gatekeeper for the paracellular pathway, and helps in preserving tissue homeostasis. TJ proteins are involved in maintaining cell polarity, in establishing organ-specific apical domains and also in recruiting signaling proteins involved in the regulation of various important cellular functions including proliferation, differentiation, and migration. As a vital component of the epithelial barrier, TJs are under a constant threat from proinflammatory mediators, pathogenic viruses and bacteria, aiding inflammation and the development of disease. Inflammatory bowel disease (IBD) patients reveal loss of TJ barrier function, increased levels of proinflammatory cytokines, and immune dysregulation; yet, the relationship between these events is partly understood. Although TJ barrier defects are inadequate to cause experimental IBD, mucosal immune activation is changed in response to augmented epithelial permeability. Thus, the current studies suggest that altered barrier function may predispose or increase disease progression and therapies targeted to specifically restore the barrier function may provide a substitute or supplement to immunologic-based therapies. This review provides a brief introduction about the TJs, AJs, structure and function of TJ proteins. The link between TJ proteins and key signaling pathways in cell proliferation, transformation, and metastasis is discussed thoroughly. We also discuss the compromised intestinal TJ integrity under inflammatory conditions, and the signaling mechanisms involved that bridge inflammation and cancer.