Colonization resistance (CR) is the ability of the gut microbiota to prevent pathogen colonization. Recent advances in technologies such as next-generation sequencing, gnotobiotic mouse models, and bacterial cultivation have enhanced understanding of the mechanisms and interactions involved in CR. CR is now understood to arise from dynamic interactions between microbes and the host, shaped by metabolic, immune, and environmental factors. This review highlights how these factors interact to either promote or impede enteric infections and discusses future research directions to understand the complex relationship between host, microbiota, and environmental determinants in safeguarding against GI infections. Microbial mechanisms of CR include resource competition and interference competition. Resource competition involves the depletion of nutrients by commensal bacteria, limiting pathogen access. Interference competition includes the production of antimicrobial compounds such as bacteriocins and T6SSs, which inhibit pathogen growth. Microbial metabolites such as short-chain fatty acids (SCFAs) and bile acids also play a role in CR. The microbiome can serve as a metric for CR, offering insights into an individual's susceptibility to infections. Diet significantly influences the nutritional landscape of the intestinal tract and can affect CR. Dietary compounds can disrupt the gut microbiome and alter the mucosal barrier, epithelial metabolism, and immune responses. Prebiotics such as inulin and pectin promote the growth of beneficial bacteria, enhancing CR against pathogens. Dietary emulsifiers and non-nutritive sweeteners can modify bacterial populations and alter gut microbiome composition. Caloric restriction and fasting can enhance CR by reducing virulence gene expression and suppressing pathogen invasion. The host immune system plays a crucial role in shaping the intestinal environment, with immune responses influencing microbiome composition and pathogen susceptibility. Host genetics also impact the gut microbiome and susceptibility to pathogen colonization, with certain genetic variants linked to altered microbiome composition and increased susceptibility to infections. Age-specific characteristics of infection susceptibility and delivery mode (e.g., cesarean section) also influence microbiome composition and infection risk. The infant microbiome undergoes unique developmental phases, with early colonization by bifidobacteria playing a key role in subsequent microbiome development. Ecological cues such as priority effects and niche modification influence pathogen colonization and microbial interactions in the gut. Understanding these factors is essential for developing strategies to enhance CR and promote human health.Colonization resistance (CR) is the ability of the gut microbiota to prevent pathogen colonization. Recent advances in technologies such as next-generation sequencing, gnotobiotic mouse models, and bacterial cultivation have enhanced understanding of the mechanisms and interactions involved in CR. CR is now understood to arise from dynamic interactions between microbes and the host, shaped by metabolic, immune, and environmental factors. This review highlights how these factors interact to either promote or impede enteric infections and discusses future research directions to understand the complex relationship between host, microbiota, and environmental determinants in safeguarding against GI infections. Microbial mechanisms of CR include resource competition and interference competition. Resource competition involves the depletion of nutrients by commensal bacteria, limiting pathogen access. Interference competition includes the production of antimicrobial compounds such as bacteriocins and T6SSs, which inhibit pathogen growth. Microbial metabolites such as short-chain fatty acids (SCFAs) and bile acids also play a role in CR. The microbiome can serve as a metric for CR, offering insights into an individual's susceptibility to infections. Diet significantly influences the nutritional landscape of the intestinal tract and can affect CR. Dietary compounds can disrupt the gut microbiome and alter the mucosal barrier, epithelial metabolism, and immune responses. Prebiotics such as inulin and pectin promote the growth of beneficial bacteria, enhancing CR against pathogens. Dietary emulsifiers and non-nutritive sweeteners can modify bacterial populations and alter gut microbiome composition. Caloric restriction and fasting can enhance CR by reducing virulence gene expression and suppressing pathogen invasion. The host immune system plays a crucial role in shaping the intestinal environment, with immune responses influencing microbiome composition and pathogen susceptibility. Host genetics also impact the gut microbiome and susceptibility to pathogen colonization, with certain genetic variants linked to altered microbiome composition and increased susceptibility to infections. Age-specific characteristics of infection susceptibility and delivery mode (e.g., cesarean section) also influence microbiome composition and infection risk. The infant microbiome undergoes unique developmental phases, with early colonization by bifidobacteria playing a key role in subsequent microbiome development. Ecological cues such as priority effects and niche modification influence pathogen colonization and microbial interactions in the gut. Understanding these factors is essential for developing strategies to enhance CR and promote human health.