Sustainable agriculture is being recognized as a method to address the increasing global food demand while reducing the negative effects of artificial fertilizers and pesticides on the environment. Using agriculturally significant bacteria as biofertilizers and biopesticides and ensuring eco-friendly agricultural practices has become a promising and comprehensive strategy. A combination of technological advancements and environmentally conscious farming methods is necessary to increase harvest yields in light of the world’s growing population and limited amount of arable land. This chapter focuses on the variety of plant and soil microbiomes and their interactions with plants. Additionally, it examines historical and current methods of harnessing their influence for sustainable agriculture while exploring the utilization of advanced techniques, such as omics technologies, to understand the molecular-level interactions between these two entities, both in a positive and/or a negative manner. Novel opportunities for environmentally responsible farming will arise from our growing knowledge of plant-microbe interactions and genes associated in these interactions. This chapter is a must-read for anyone doing research in the areas of plant science, agricultural microbiology, plant engineering technology, plant-microbe interactions, and related disciplines. Graduate students and faculty in the areas of biotechnology, microbiology, biochemistry, and agricultural science will find it valuable.