Chronic Rhinosinusitis (CRS) is characterized by edema of the sub-epithelial layers, but, only specific types of CRS are developing polyps. Nasal polyposis may develop under different pathogenetic mechanisms rendering the typical macroscopic classification of CRS, with or without nasal polyps, rather deficient. Currently, we approach nasal polyposis, in terms of diagnosis and treatment, according to its endotype, which means that we focus on the specific cells and cytokines that are participating in its pathogenesis. It appears that the molecular procedures that contribute to polyp formation, initiating with a Th-2 response of the adaptive immune system, are local phenomena occurring in the sub-epithelial layers of the mucosa. Several hypotheses are trying to approach the etiology that drives the immune response towards Th-2 type. Extrinsic factors, like fungi, Staphylococcus superantigens, biofilms, and altered microbiome can contribute to a modified and intense local reaction of the immune system. Some hypotheses based on intrinsic factors like the elimination of Treg lymphocytes, low local vitamin-D levels, high levels of leukotrienes, epithelial to mesenchymal transition (EMT) induced by hypoxia, and altered levels of NO, add pieces to the puzzle of the pathogenesis of nasal polyposis. Currently, the most complete theory is that of epithelial immune barrier dysfunction. Intrinsic and extrinsic conditions can damage the epithelial barrier rendering sub-epithelial layers more vulnerable to invasion by pathogens that trigger a Th-2 response of the adaptive immune system. Th2 cytokines, subsequently, induce the accumulation of eosinophils and IgE together with the remodeling of the stroma in the sub-epithelial layers leading, eventually, to the formation of nasal polyps.