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Luisa Bertin,1 Martina Crepaldi,1 Miriana Zanconato,1 Greta Lorenzon,1 Daria Maniero,1 Caterina De Barba,1 Erica Bonazzi,1 Sonia Facchin,1 Marco Scarpa,2 Cesare Ruffolo,2 Imerio Angriman,2 Andrea Buda,3 Fabiana Zingone,1 Edoardo Vincenzo Savarino,1 Brigida Barberio1 1Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; 2Chirurgia Generale 3 Unit, Azienda Ospedale Università di Padova, Padua, Italy; 3Gastroenterology Unit, Department of Oncological Gastrointestinal Surgery, Feltre, ItalyCorrespondence: Edoardo Vincenzo Savarino, Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy, Tel +39-049-8217749, Fax +39-049-8760820, Email edoardo.savarino@unipd.itAbstract: Crohn’s disease (CD) is a complex, chronic inflammatory bowel disease characterized by unpredictable flare-ups and periods of remission. Despite advances in treatment, CD remains a significant health burden, leading to substantial direct healthcare costs and out-of-pocket expenses for patients, especially in the first-year post-diagnosis. The impact of CD on patients’ quality of life is profound, with significant reductions in physical, emotional, and social well-being. Despite advancements in therapeutic options, including biologics, immunomodulators, and small molecules, many patients struggle to achieve or maintain remission, leading to a considerable therapeutic ceiling. This has led to an increased focus on novel and emerging treatments. This context underscores the importance of exploring advanced and innovative treatment options for managing refractory CD. By examining the latest approaches, including immunomodulators, combination therapies, stem cell therapies, and emerging treatments like fecal microbiota transplantation and dietary interventions, there is an opportunity to gain a comprehensive understanding of how best to address and manage refractory cases of CD. Keywords: refractory Crohn’s disease, mesenchymal stem cell therapy, medical therapy, combination therapy, fecal microbiota transplantation, biologic drugs, perianal Crohn’s disease, small molecules, hyperbaric oxygen therapy