ABSTRACT: Some plant growth promoting bacteria (PGPB) do not need to colonize plant roots to trigger the growth promotion mechanisms, as they emit volatile organic compounds (VOCs), which are small gaseous signaling molecules that mediate short- and long-distance interactions between plants and microorganisms. Therefore, VOCs-producing PGPB can be an eco-friendly solution to increase agricultural production. We aimed to understand the mechanisms underlying the VOC-mediated growth promotion effect on Setaria viridis, a model plant of C4 metabolism, by investigating its molecular, cellular, physiological and phenotypical changes triggered by these bioactive compounds. Remarkably, we screened and selected two bacteria, Pseudomonas and Burkholderia, capable of increasing the biomass of S. viridis plants by up to 4-fold in a co-cultivation system, wherein plant and bacteria only share the same atmosphere. A total of 2,871 differentially expressed genes (DEGs) were identified in S. viridis plants when exposed to VOCs from at least one of the three isolates (AI2, CTB and MTS) compared to the mock control. Then, a Gene Ontology analysis was performed. Comparing AI2 and mock treatment, 80 and 26 up- and down-regulated GOs were identified, respectively, while when comparing CTB and mock treatment, 94 up- and 36 down-regulated GOs were identified. Among these differential GOs in at least one of the growth promotion treatments compared to one or both controls we found categories like “aromatic compound biosynthetic process” (GO:0019438), “abscisic acid binding” (GO:0010427), "systemic acquired resistance" (GO:0009627), and “chitin catabolic process” (GO:0006032). Other GOs were only regulated in the treatments containing bacteria, such as “sucrose biosynthetic process” (GO:0005986), “L-phenylalanine metabolic process” (GO:0006558), “cell surface receptor signaling pathway” (GO:0007166), and “regulation of nitrogen compound metabolic process” (GO:0051171). Overall, the enrichment analysis showed a diverse spectrum of categories related to primary and secondary metabolisms, hormone pathways, enzymatic activities, plant defense and resistance, among others. Together with the other omic and target analyses, the study suggests that bacterial VOCs were able to boost photosynthesis, increasing the sugar content, that fuels respiration and cell wall modulation. Besides, VOCs were able to trigger defense response.