Mycoplasma genomes were long thought to be shaped exclusively by successive gene losses. In-depth analyses of Mycoplasma genomes have clearly demonstrated the contribution of horizontal gene transfer (HGT) to the evolution and plasticity of many mycoplasma species. Therefore, HGT may be used by mycoplasmas as a mean to rapidly adapt to new environmental stresses or ecological niches. A recent effort to sequence and analyze the genomes of 24 Mycoplasma (M.) equirhinis, a species associated with the equine respiratory disease complex in horses, revealed that all these genomes are overall syntenic except for a few regions, one of which is adjacent to the CRISPR/Cas locus (Martineau et al., IOM submission number 80). This locus scrutinized in silico turned out to be highly variable between the 24 genomes with eight different genetic patterns resulting from rearrangements affecting i) the presence and/or general genetic organization of the CRISPR/Cas locus, but also ii) the genomic region downstream of the CRISPR/Cas locus, which was defined as a hot spot of genetic diversity. Remarkably, all the genes downstream of the CRISPR/Cas system were horizontally acquired and appeared to originate from bacteria belonging to the Bacillota and Fusobacteriota phyla. In silico analyses further revealed that some of the coding sequences present in these regions shared high homologies with previously described defense mechanisms such as restriction-modification or toxin-antitoxin (TA) systems. In particular, the presence of at least one candidate TA system was identified in half of the genomes with high amino acid homology to one of the TA systems functionally characterized in M. mycoides subsp. capri (1). Its functional characterization is currently ongoing using different heterologous expression systems. These results suggest that M. equirhinis can acquire and potentially exchange genetic material with other phylogenetically distant bacteria that share the same ecological niche, i.e. the equine respiratory tract. The coding sequences located in this hotspot of recombination have putative functions linked to bacterial defense systems.