Prokaryotes evolve not only through mutation, but also by extensive horizontal gene transfer mediated by mobile genetic elements (MGEs). These lateral transfer processes have received increasing attention due to their role in driving the spread of antimicrobial resistance (AMR) genes, contributing to the current global health crisis. As MGEs can be highly costly to the host cell, prokaryotes have evolved a diverse arsenal of defences against them. This thesis explores various aspects of this evolutionary arms race, as well as what it means for the AMR crisis. Firstly, I investigated the distribution of acquired AMR genes, multidrug resistance, and resistance genes of global concern across phylogroups, geographic subregions, temperatures and host types in ~16,000 Escherichia coli genomes. The results mapped AMR incidence across E. coli, with diverse findings including higher levels of AMR in commensal lineages, wild bird hosts and with increasing temperature. Next, I explored the impact of the bacterial immune system CRISPR-Cas on the acquisition of MGEs and AMR genes in ~40,000 genomes from various pathogenic species. This revealed an absence of CRISPR-Cas systems in genomes with many AMR genes, as well as finding spacers that directly target MGEs for removal in genomes where CRISPR-Cas was present, suggesting an “immunocompromised” state for multidrug-resistant bacteria. Subsequently, I reviewed the potential challenges and future directions for research into CRISPR-Cas antimicrobials, highlighting key hurdles such as developing successful MGE-based delivery vectors. Finally, I characterised the novel bacterial immune system Maestri using remote homology predictions about the proteins in its 8-gene defence operon. This identified key components typically found in bacterial immune systems such as a putative restriction enzyme, methyltransferase and protein kinase. I used macromolecular models to determine the distribution of Maestri in over 250,000 prokaryotic genomes, finding the system in diverse bacterial classes. Overall, this thesis shows the extensive distribution of AMR in a key pathogen and the role of CRISPR-Cas in potentially blocking AMR acquisition, as well as characterising a novel bacterial immune system to add to the growing arsenal of known genome defences that influence the flow of genes in bacteria. As well as developing and using methods to investigate AMR distribution and host-MGE coevolution in large datasets, this work also highlights important factors for the design of novel MGE-based antibiotic alternatives, such as phage therapy and CRISPR-Cas antimicrobials. Understanding the dynamics of bacterial genome evolution via horizontal gene transfer is key to combatting the AMR crisis.