Plants have evolved a complex and elaborate signaling network to respond appropriately to the pathogen invasion by regulating expression of defensive genes through certain transcription factors. The APETALA2/ethylene response factor (AP2/ERF) family members have been determined as key regulators in growth, development, and stress responses in plants. Moreover, a growing body of evidence has demonstrated the critical roles of AP2/ERFs in plant disease resistance. In this review, we describe recent advances for the function of AP2/ERFs in defense responses against microbial pathogens. We summarize that AP2/ERFs are involved in plant disease resistance by acting downstream of mitogen activated protein kinase (MAPK) cascades, and regulating expression of genes associated with hormonal signaling pathways, biosynthesis of secondary metabolites, and formation of physical barriers in an MAPK-dependent or -independent manner. The present review provides a multidimensional perspective on the functions of AP2/ERFs in plant disease resistance, which will facilitate the understanding and future investigation on the roles of AP2/ERFs in plant immunity.