The human interface with the microbial world has so far largely been considered through the somewhat restrictive angle of host-pathogen interactions resulting in disease. It has consequently largely ignored the daily symbiosis with the microbiota, an ensemble of symbiotic microorganisms engaged in a commensal, and for some of them mutualistic, interaction. This microbiota heavily populates essential surfaces such as the oral and intestinal cavity, the upper respiratory tract, the vagina, and the skin. Host response to the pathogens is characterized by quick recognition combined with strong innate (i.e., inflammatory) and adaptive immune responses, causing microbial eradication often at the cost of significant tissue damage. Response to the symbiotic microbiota is characterized by a process called tolerance that encompasses a complex integration of microbial recognition and tightly controlled innate (i.e., physiological inflammation) and adaptive immune responses. This dichotomy in host response is critical at the gut mucosal surface that is massively colonized by a diverse population of bacteria. The host is therefore permanently facing the challenge of discriminating among symbiotic and pathogenic bacteria in order to offer an adapted response. This asks the fundamental existential question: "to be or not to be… a pathogen." This review has attempted to consider this question from the host angle. What do host mucosal sensing systems see in the bacteria to which they become exposed to establish proper discrimination? A new facet of medicine resides in the dysfunction of this complex balance that has likely forged the complexity of the immune system.