The social movement to reduce reliance on pesticides and synthesized fertilizers and the growing global demand for sustainable food supplies require the development of eco‐friendly and sustainable agricultural practices. In line, plant growth‐promoting bacteria (PGPB) can participate in creating innovative agroecological systems. While the effectiveness of PGPB is highly influenced by abiotic conditions and microbe–microbe interactions, beneficial plant–PGPB interactions can also highly depend on both host and PGPB genotype. Here, the state of the art on the extent of natural genetic variation of plant–PGPB interactions and the underlying genetic architecture, in particular in Arabidopsis thaliana is reviewed. Extensive natural plant genetic variation in response to PGPB is associated with a polygenic architecture and genetic pathways rarely mentioned as being involved in the response to PGPB. To date, natural genetic variation within PGPB is little explored, which may in turn allow the identification of new genetic pathways underlying benefits to plants. Accordingly, several avenues to better understand the genomic and molecular landscape of plant–PGPB interactions are introduced. Finally, the need for establishing thorough functional studies of candidate genes underlying Quantitative Trait Loci and estimating the extent of genotype‐by‐genotype‐by‐environment interactions within the context of realistic (agro‐)ecological conditions is advocated.