Recent advances in the study of nucleic acid modifications, such as N6-methyladenosine (m6A) in RNA and 5-methylcytosine (5mC) in DNA, have significantly enhanced our understanding of the complex mechanisms regulating plant–microbe interactions. The major epitranscriptomic mark m6A has been implicated in immune responses against diverse pathogens, including viruses, bacteria, fungi, and oomycetes. Additionally, DNA methylation and histone modifications epigenetically control plant gene expression upon pathogen attack and during interaction with beneficial microbes. The chapter discusses the current state of knowledge on epitranscriptomic and epigenetic mechanisms that regulate plant–microbe interactions, which may ultimately lead to novel strategies for crop health management and for enhancing crop productivity.