The rhizosphere, the thin layer of soil that surrounds plant roots, is a microbial hotspot, and this root microbime strongly influences plant health. The rapid development of next generation sequencing technologies and advanced bioinformatic platforms have revolutionized our capacity to analyze and understand microbiomes in complex agro-ecosystems including the rhizosphere. This article reviews these technologies and presents two studies conducted in our lab that demonstrate how extensive understanding of the rhizosphere microbiome can be exploited to facilitate environmentally sustainable solutions for mitigating plant disease. The first study reveals how shifts in microbial community composition and increased microbial diversity in the rhizosphere facilitate plant resistance to certain pathogens, while the second targets rhizosphere microbiomes to discover novel antimicrobial compounds that can be isolated and applied to treat plant disease.