Simple SummaryThe role of gut microbiota and environmental factors on IBD-related CRC is still a burning question. Crohn’s Disease (CD) and Ulcerative Colitis (UC) are complex disorders, widely known to increase the risk of CRC development as a consequence of the enteric chronic inflammation status, which determines dysplasia, finally resulting in carcinoma. CRC in IBD patients shows multiple distinctive features compared with sporadic CRC, some of which have not fully been understood so far. In this context, an imbalance in gut microbiota composition (also known as dysbiosis) can be pivotal in promoting both inflammation and tumorigenesis through several and complex pathways embracing host genetics and environmental factors, including diabetes, obesity, diet (i.e., meat consumption, vitamin intake) and smoking. As the following review shows, the intriguing interconnections between gut microbiota and environment and their role in tumorigenesis have been mostly investigated in animal and in vitro models, so future research on human beings is needed to apply collected data in clinical practice.AbstractColo-rectal cancer (CRC) is undoubtedly one of the most severe complications of inflammatory bowel diseases (IBD). While sporadic CRC develops from a typical adenoma-carcinoma sequence, IBD-related CRC follows different and less understood pathways and its pathophysiological mechanisms were not completely elucidated. In contrast to chronic inflammation, which is nowadays a well-recognised drive towards neoplastic transformation in IBD, only recently was gut microbiota demonstrated to interfere with both inflammation processes and immune-mediated anticancer surveillance. Moreover, the role of microbiota appears particularly complex and intriguing when also considering its multifaceted interactions with multiple environmental stimuli, notably chronic pathologies such as diabetes and obesity, lifestyle (diet, smoking) and vitamin intake. In this review, we presented a comprehensive overview on current evidence of the influence of gut microbiota on IBD-related CRC, in particular its mutual interconnections with the environment.