We are in the midst of a golden age of uncovering defense systems against bacteriophages. Apart from the fundamentalinterest in these defense systems, and revolutionary applications that have been derived from them (e.g. CRISPR-Cas9 andrestriction endonucleases), it is unknown how defense systems contribute to resistance formation against bacteriophagesin clinical settings. Bacteriophages are now being reconsidered as therapeutic agents against bacterial infections due the
emergence of multidrug resistance. However, bacteriophage resistance through defense systems and other means couldhinder the development of successful phage-based therapies. Here, we review the current state of the field of bacteriophagedefense, highlight the relevance of bacteriophage defense for potential clinical use of bacteriophages as therapeutic agentsand suggest new directions of research.