<p>Inflammatory bowel disease (IBD) is a complex, multifactorial inflammatory disorder of the gut characterized by an imbalance in host–microbiota interactions. Here, we review how early events of IBD are shaped by gene–environment interactions, especially those involving microbial perturbations. Those perturbations eventually lead to chronic inflammation and tissue damage of the gastrointestinal tract. IBD is a multi-hit process in which infectious and noninfectious agents initiate a cascade of immune activation in genetically susceptible individuals. Ultimately the process results in irreversible immunological and physical scarring. These interactions are host specific, with genetic variants influencing the threshold for immune activation and the degree of damage, thus leading to variability in disease progression and therapeutic outcomes. Finally, we discuss challenges, including addressing health disparities and potential strategies for more personalized and effective therapies that target host–microbiota interactions during the preclinical phase of IBD.</p>