The co-existence of plants and microorganisms throughout their evolution resulted in an intertwined ecological network that serves as the basis for the functioning of today’s terrestrial ecosystems. The interactions between plants, bacteria, and fungi are often multipartite and occur both within and among kingdoms. Apart from the textbook examples of tight mutualistic associations such as root nodule symbiosis or mycorrhizas, there are also looser interactions, e.g., those between plants and plant growth-promoting bacteria and fungi. Additionally, plants are also targets of microbial pathogens. Thus, intricate mechanisms of how plants and microorganisms recognize each other have evolved, mediated by chemical signals resulting in a differential gene expression and, eventually, a physiological response. This paper aims to review the molecular basis of such signaling, the apparatus of signal sensing and transduction in bacteria and plants are outlined and exemplified. Moreover, examples of recent discoveries in the field of plant–microbe signaling are presented, i.e., quorum quenching and the involvement of small RNAs. Last but not least, suggestions are provided for the potential exploitation of plant–microbe communication networks for human benefit, e.g., in the field of sustainable agriculture, aiming at crop growth promotion and protection against pathogens.