Non-celiac gluten sensitivity (NCGS) is the term used to describe individuals complaining of intestinal and extra-intestinal symptoms related to gluten ingestion and rapidly improving after its withdrawal, and in which both celiac disease (CD) and wheat-allergy (WA) were properly ruled out. The prevalence of this condition remains unknown and a lot of questions about the possible pathogenetic mechanisms are still unclarified. It is believed that NCGS represents a heterogeneous condition with different subgroups potentially characterized by different pathogenesis, clinical history, and clinical course. Moreover, a possible overlap with irritable bowel syndrome (IBS) and other functional diseases could complicate patient selection for clinical studies, slowing down the understanding of this disorder. Last but not least, the lack of validated biomarkers remains a significant limitation in research studies on NCGS. IIence, there is a need for strict diagnostic criteria for NCGS.