The "keystone pathogen" hypothesis posits that certain low-abundance microbial pathogens can orchestrate inflammatory disease by transforming a normally benign microbiota into a dysbiotic one. This hypothesis suggests that these pathogens, despite their low abundance, have a disproportionately large impact on host health and disease. The authors critically review the literature supporting this hypothesis, particularly in the context of periodontitis, inflammatory bowel disease (IBD), colon cancer, and obesity. They highlight the role of specific pathogens, such as *Porphyromonas gingivalis* in periodontitis and *Klebsiella pneumoniae* and *Proteus mirabilis* in IBD, which can induce dysbiosis and promote inflammation. The hypothesis also extends to other conditions, such as colon cancer, where pro-oncogenic bacteria like *Bacteroides fragilis* may act as "alpha-bugs" by collaborating with the colonic microbiota to promote carcinogenesis. The authors discuss the potential clinical implications of identifying keystone pathogens, including the development of targeted diagnostic tools and treatments for complex dysbiotic diseases. They emphasize the need for further research to understand the mechanisms by which these pathogens cause disease and to explore the role of host factors in susceptibility or resistance to their effects.The "keystone pathogen" hypothesis posits that certain low-abundance microbial pathogens can orchestrate inflammatory disease by transforming a normally benign microbiota into a dysbiotic one. This hypothesis suggests that these pathogens, despite their low abundance, have a disproportionately large impact on host health and disease. The authors critically review the literature supporting this hypothesis, particularly in the context of periodontitis, inflammatory bowel disease (IBD), colon cancer, and obesity. They highlight the role of specific pathogens, such as *Porphyromonas gingivalis* in periodontitis and *Klebsiella pneumoniae* and *Proteus mirabilis* in IBD, which can induce dysbiosis and promote inflammation. The hypothesis also extends to other conditions, such as colon cancer, where pro-oncogenic bacteria like *Bacteroides fragilis* may act as "alpha-bugs" by collaborating with the colonic microbiota to promote carcinogenesis. The authors discuss the potential clinical implications of identifying keystone pathogens, including the development of targeted diagnostic tools and treatments for complex dysbiotic diseases. They emphasize the need for further research to understand the mechanisms by which these pathogens cause disease and to explore the role of host factors in susceptibility or resistance to their effects.