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Probiotics have been used to treat a variety of diseases for decades; however, what is the rationale for their application? Such a treatment was first proposed in the early nineteenth century based on observations of decreased bifidobacterial populations in children suffering from diarrhea, suggesting that oral intake of bifidobacteria could replete this subpopulation of the microbiota and improve health. Since then, studies have shown modifications in the gut or skin microbiota in the course of a variety of diseases and suggested positive effects of certain probiotics. Most studies failed to report any impact on the microbiota. The impact of probiotics as well as of bacteria colonizing food does not reside in their ability to graft in the microbiota but rather in sharing genes and metabolites, supporting challenged microbiota, and directly influencing epithelial and immune cells. Such observations argue that probiotics could be associated with conventional drugs for insulin resistance, infectious diseases, inflammatory diseases, and psychiatric disorders and could also interfere with drug metabolism. Nevertheless, in the context of a plethora of probiotic strains and associations produced in conditions that do not allow direct comparisons, it remains difficult to know whether a patient would benefit from taking a particular probiotic. In other words, although several mechanisms are observed when studying a single probiotic strain, not all individual strains are expected to share the same effects. To clarify the role of probiotics in the clinic, we explored the relation between probiotics and the gut and skin microbiota.