Gluten has multiple harmful effects that compromise human health, not only in gluten-dependent diseases but also in non- gluten-affected chronic inflammatory conditions. After consumption, the indigestible gluten peptides are modified by luminal microbial transglutaminase or transported through the gut epithelium to interact with the highly populated mucosal immune cells. As a disruptor of gut permeability, gluten peptides compromise tight junction integrity, allowing foreign immunogenic molecules to reach internal compartments. Gliadin peptides are distributed systemically to remote organs, where they encounter endogenous tissue transglutaminase. Following post-translational deamidation or transamidation, the peptides become immunogenic and pro-inflammatory, inducing organ dysfunction and pathology. Cross-reactivity and sequence homology between gluten/gliadin peptides and human epitopes may contribute to molecular mimicry in autoimmunity induction. A gluten-free diet can prevent these phenomena through various mechanisms. As proof of concept, gluten withdrawal alleviates disease activity in chronic inflammatory, metabolic, and autoimmune conditions, and even in neurodegeneration. We recommend combining the gluten-free and Mediterranean diets to leverage the advantages of both. Before recommending gluten withdrawal for non-gluten-dependent conditions, patients should be asked about gut symptomatology and screened for celiac-associated antibodies. The current list of gluten-induced diseases includes celiac disease, dermatitis herpetiformis, gluten ataxia, gluten allergy, and non-celiac gluten sensitivity. In view of gluten being a universal pro-inflammatory molecule, other non-celiac autoinflammatory and neurodegenerative conditions should be investigated for potential gluten avoidance.