Globally rising rates of resistance against all major classes of chemotherapeutic antibiotics has renewed interest in the therapeutic use of phages to treat bacterial infections. As with antibiotic treatments, the emergence of bacterial resistance against phage treatments could also limit the long-term sustainability of phage-based therapeutics. We currently lack a mechanistic understanding of how bacteria evolve resistance against combinations of multiple phages, limiting our ability to design phage combinations that limit resistance. Importantly, bacteria possess multiple distinct mechanisms to defend against phage infection, including surface receptor modification (SRM) and CRISPR-Cas. These distinct mechanisms are favoured under different conditions which are likely to vary at the site of infection, but the importance of CRISPR-Cas for the evolution of resistance against phage therapy is unknown. We will use laboratory evolution experiments to determine how CRISPR-Cas immunity affects the evolution of multi-phage resistance across infection-relevant environmental conditions predicted to tip the balance from SRM to CRISPR-Cas immunity. We will then test if, by enhancing multi-phage resistance evolution, CRISPR-Cas immunity reduces the efficacy of phage therapy in vivo using a mouse model of acute respiratory infection. These experiments will develop and test an evolutionary framework for understanding how CRISPR-Cas affects multi-phage resistance evolution and the efficacy of phage therapy.