Omics approaches, especially targeting genome editing, have generated considerable interest in crop improvement in agriculture. Plant-pathogen interaction is crucial for inducing a defense response and disease development. Plants use signaling molecules called pathogen-associated molecular patterns (PAMP)-triggered immunity (PTI) and effector-triggered immunity (ETI) to recognize and identify invading pathogens. CRISPR, or clustered regularly interspaced short palindromic repeats, is a popular genomic editing technology utilized in both prokaryotes and eukaryotes. CRISPR/Cas9 is a synthetic endonuclease with palindromic repeats that can be reprogrammed into various genome editing tools. CRISPR is simple, versatile, and highly efficient for gene knockout, targeting major susceptibility genes and negative regulators of host defense pathways for gaining resistance to bacterial, fungal, and viral pathogens in plants. This chapter explains the fundamentals of developing CRISPR-based tools and how they may be used to improve crops. It also covers tests that are aimed at plant pathogens and other possible uses in pest management and plant-pathogen interactions that will enhance plant breeding for crop protection.