This article proposes an extension of the hygiene hypothesis to explain chronic inflammatory diseases (CIDs) and their increase with westernization. Instead of emphasizing microbes that are missing/reduced due to westernization, a hypothesis is proposed that emphasizes the importance of microbes that are relatively novel. Environmental microbes encountered in association with a pre-agricultural lifestyle would presumably be the most coevolved with the human immune system and thus less likely to promote chronic disease. Post-hunter-gatherer era microbes (PHMs) are microbes that are encountered more frequently and/or at higher levels since humans ceased to live as nomadic hunter-gatherers. It is hypothesized that some PHMs, particularly those increasing with westernization, colonize human tissues and dysregulate/suppress the immune system. This hypothesized colonization of PHMs could cause allergy/hypersensitivity reactions leading to physiological stress, attacks on self-tissue, hypersensitivity reactions to similar cross-reacting environmental microbes and other allergens/antigens, greater vulnerability to diverse infections (e.g., COVID-19) and CIDs. Low-level colonization with diverse PHMs could explain high levels of comorbidities among CIDs, allergic responses to self-tissue (auto allergy), allergies to varied microbial taxa and allergen-initiated stress effects. Allergic reactions and the stress they cause might be adaptive by promoting expulsion and avoidance of potentially dangerous microbes. This is consistent with the observation that selective IgE deficiency leads to increased levels of diseases such as asthma, chronic rhinosinusitis, otitis media and autoimmune disease. PHMs that could be related to CIDs include microbes in tobacco smoke, increased Candida albicans and Aspergillus fumigatus that occurs in some situations, and increased exposure to Pseudomonas fluorescens and Yersinia spp. Additionally, fungi that tolerate multiple extreme environments have been found to be more likely to be opportunistic pathogens. This might suggest that microbes associated with human-created novel and extreme environments (e.g., antibiotics, xenobiotics) would have an increased ability to colonize and persist in humans. The PHM hypothesis could help explain contradictory findings on diet, why many chronic inflammatory diseases resemble chronic infections and why stress and xenobiotics are associated with CID incidence and exacerbations. Four foundations and 11 related hypotheses are discussed. Examples discussed include sarcoidosis, inflammatory bowel disease, asthma, long-term COVID-19 and Kawasaki disease.