The gastrointestinal (GI) tract is colonized by a complex microbial community that plays a crucial role in protecting hosts from pathogenic bacteria through a mechanism known as colonization resistance (CR). Advances in technologies such as next-generation sequencing, gnotobiotic mouse models, and bacterial cultivation have enhanced our understanding of the underlying mechanisms and the intricate microbial interactions involved in CR. CR is not attributed to specific microbial clades but arises from a dynamic interplay between microbes and the host, shaped by metabolic, immune, and environmental factors. This review highlights recent research that has shifted its focus toward elucidating how these factors interact to either promote or impede enteric infections. It discusses the role of microbial mechanisms, including resource competition and interference competition, in establishing conditions that exclude pathogens from the GI tract. The review also explores the impact of contextual factors, such as diet, host genetics, and age, on CR. Additionally, it examines the role of the immune system, particularly the intestinal IgA response, in shaping the intestinal environment and influencing pathogen susceptibility. Finally, the review addresses the effects of drugs and phages on the gut microbiome and the implications for CR.The gastrointestinal (GI) tract is colonized by a complex microbial community that plays a crucial role in protecting hosts from pathogenic bacteria through a mechanism known as colonization resistance (CR). Advances in technologies such as next-generation sequencing, gnotobiotic mouse models, and bacterial cultivation have enhanced our understanding of the underlying mechanisms and the intricate microbial interactions involved in CR. CR is not attributed to specific microbial clades but arises from a dynamic interplay between microbes and the host, shaped by metabolic, immune, and environmental factors. This review highlights recent research that has shifted its focus toward elucidating how these factors interact to either promote or impede enteric infections. It discusses the role of microbial mechanisms, including resource competition and interference competition, in establishing conditions that exclude pathogens from the GI tract. The review also explores the impact of contextual factors, such as diet, host genetics, and age, on CR. Additionally, it examines the role of the immune system, particularly the intestinal IgA response, in shaping the intestinal environment and influencing pathogen susceptibility. Finally, the review addresses the effects of drugs and phages on the gut microbiome and the implications for CR.