Drought generates a complex scenario worldwide in which agriculture should urgently be reframed from an integrative point of view. It includes the search for new water resources and the use of tolerant crops and genotypes, improved irrigation systems, and other less explored alternatives that are very important, such as biotechnological tools that may increase the water use efficiency. Currently, a large body of evidence highlights the role of specific strains in the main microbial rhizosphere groups (arbuscular mycorrhizal fungi, yeasts, and bacteria) on increasing the drought tolerance of their host plants through diverse plant growth-promoting (PGP) characteristics. With this background, it is possible to suggest that the joint use of distinct PGP microbes could produce positive interactions or additive beneficial effects on their host plants if their co-inoculation does not generate antagonistic responses. To date, such effects have only been partially analyzed by using single omics tools, such as genomics, metabolomics, or proteomics. However, there is a gap of information in the use of multi-omics approaches to detect interactions between PGP and host plants. This approach must be the next scale-jump in the study of the interaction of soil–plant–microorganism. In this review, we analyzed the constraints posed by drought in the framework of an increasing global demand for plant production, integrating the important role played by the rhizosphere biota as a PGP agent. Using multi-omics approaches to understand in depth the processes that occur in plants in the presence of microorganisms can allow us to modulate their combined use and drive it to increase crop yields, improving production processes to attend the growing global demand for food.