Pathogenic microorganisms and insects affecting plant health are a major and chronic threat to food production and the ecosystem worldwide. As agricultural production has intensified over the years, the use of agrochemicals has in turn increased. However, this extensive usage has had several detrimental effects, with a pervasive environmental impact and the emergence of pathogen resistance. In addition, there is an increasing tendency among consumers to give preference to pesticide-free food products. Biological control, through the employment of plant growth-promoting rhizobacteria (PGPR), is therefore considered a possible route to the reduction, even the elimination, of the use of agrochemicals. PGPR exert their beneficial influence by a multitude of mechanisms, often involving antibiotics and proteins, to defend the host plant against pathogens. To date, these key metabolites have been uncovered only by systematic investigation or by serendipity; their discovery has nevertheless been propelled by the genomic revolution of recent years, as increasing numbers of genomic studies have been integrated into this field, facilitating a holistic view of this topic and the rapid identification of ecologically important metabolites. This review surveys the highlights and advances of genome-driven compound and protein discovery in the field of bacterial PGPR strains, and aims to advocate for the benefits of this strategy.