Mitogen-activated protein kinase (MAPK) cascades are highly conserved signaling modules downstream of receptors/sensors that transduce extracellular stimuli into intracellular responses in eukaryotes. Plant MAPK cascades play pivotal roles in signaling plant defense against pathogen attack. In this review, we summarize recent advances in the identification of upstream receptors/sensors and downstream MAPK substrates. These findings revealed the molecular mechanisms underlying MAPK functions in plant disease resistance. MAPK cascades have also emerged as battlegrounds of plant-pathogen interactions. Activation of MAPKs is one of the earliest signaling events after plant sensing of pathogen/microbe-associated molecular patterns (PAMPs/MAMPs) and pathogen effectors. MAPK cascades are involved in signaling multiple defense responses, including the biosynthesis/signaling of plant stress/defense hormones, reactive oxygen species (ROS) generation, stomatal closure, defense gene activation, phytoalexin biosynthesis, cell wall strengthening, and hypersensitive response (HR) cell death. Pathogens, however, employ effectors to suppress plant MAPK activation and downstream defense responses to promote pathogenesis.