Plant interacts with a wide range of microbes during its life cycle and shares varying ecological relationships with them. Identifying and studying plant–microbiome interactions beneficial/harmful assists in the discovery of novel microorganisms and their application besides improving the prevalent bioformulations. A better understanding of plant microbiome is a must for the development of effective biofertilizers, sustaining yield under erratic climatic conditions, and biotic stress management. Biotechnology, genetic engineering, and bioinformatics have shifted the ways and means of utilizing microorganisms from typical screening, mutagenesis, and selection toward the use of modern system biology toolbox. Recent progress made in the field of omics has unfurled the complex mechanisms regulating the mutual interaction of microbes with host plants, their influence on host metabolism, pathogenesis, etc. In addition, multiomics approaches, a combination of computational techniques, are a potential contributor to these developments helping in more precise engineering and usage of plant-associated microbes. This chapter summarizes the methods of key high throughput (“omics”) techniques and their role in studying the various aspects of plant–microbiome interaction.