Background: Histamine intolerance (HI) is a disorder caused by an impaired ability to degrade histamine, leading to an accumulation of the biogenic amine in the body.Histamine intolerance is frequently misdiagnosed or overlooked, partly due to its symptom overlap with other conditions such as food allergies, irritable bowel syndrome, and migraines. Methods: This review examines the current literature on histamine intolerance, focusing on its pathophysiology, diagnostic challenges, and therapeutic strategies. We conducted a comprehensive search of PubMed, Scopus, and other medical databases for relevant studies published in the past two decades. Key topics reviewed include the enzymatic breakdown of histamine (DAO and HNMT), clinical symptomatology, diagnostic methodologies (including dietary elimination and histamine challenge tests), and current treatment protocols such as dietary management, enzyme supplementation, and pharmacological interventions. Results: Histamine intolerance is linked to dysfunction or deficiency in the enzymes diamine oxidase (DAO) and histamine N-methyltransferase (HNMT). While diagnostic testing for HI remains challenging, many studies suggest that DAO activity levels can be a potential biomarker, though results are often inconsistent. Clinical symptoms vary widely, with gastrointestinal issues, neurological disturbances, and skin conditions (urticaria) being most commonly reported. Management typically involves a low-histamine diet and, in some cases, DAO supplementation or antihistamine therapy. Conclusion: Histamine intolerance is a complex and often underdiagnosed condition that requires a multifaceted approach for diagnosis and management. While a low-histamine diet remains the primary treatment strategy.