The complex biology of the microbiome was elucidated once the genomics era began. The proteogenomic approach analyzes and integrates genetic makeup (genomics) and microbial communities′ expressed proteins (proteomics). Therefore, researchers gained insights into gene expression, protein functions, and metabolic pathways, understanding microbial dynamics and behavior, interactions with host cells, and responses to environmental stimuli. In this context, our work aims to bring together data regarding the application of genomics, proteomics, and bioinformatics in microbiome research and to provide new perspectives for applying microbiota modulation in clinical practice with maximum efficiency. This review also synthesizes data from the literature, shedding light on the potential biomarkers and therapeutic targets for various diseases influenced by the microbiome.