In the current context of climate change, there is a need to develop more sustainable agrifood strategies. As an alternative to the intensive use of chemically synthesized fertilizers and pesticides that pollute water and impact biodiversity, there is a growing interest in using beneficial microbes as biostimulants and/or bioprotection agents. However, their implementation in agriculture remains a challenge due to highly variable outcomes and benefits. Furthermore, there are major knowledge gaps about the molecular mechanisms that regulate different plant-microbe interactions. In the present review, we summarize current knowledge on the molecular mechanisms that control different beneficial plant root-microbe interactions; namely, arbuscular mycorrhiza, the rhizobium-legume symbiosis, ectomycorrhiza, and fungal and bacterial endophytic associations. This includes the signaling pathways required for recognition of microbes as beneficial, the metabolic pathways that provide nutritional benefits to the plant, and the regulatory pathways that modulate the extent of symbiosis establishment depending on soil nutrient availability and plant needs. Our aim is to highlight the main common mechanisms, as well as knowledge gaps, in order to promote the use of microbes, either individually or in consortia, within the framework of a sustainable agriculture that is less dependent on chemicals and more protective of biodiversity and water resources.