Soil health is crucial for global food production in the context of an ever-growing global population. Microbiomes, a combination of microorganisms and their activities, play a pivotal role by biodegrading contaminants, maintaining soil structure, controlling nutrients’ cycles, and regulating the plant responses to biotic and abiotic stresses. Microbiome-based solutions along the soil-plant continuum, and their scaling up from laboratory experiments to field applications, hold promise for enhancing agricultural sustainability by harnessing the power of microbial consortia. Synthetic microbial communities, i.e., selected microbial consortia, are designed to perform specific functions. In contrast, natural communities leverage indigenous microbial populations that are adapted to local soil conditions, promoting ecosystem resilience, and reducing reliance on external inputs. The identification of microbial indicators requires a holistic approach. It is fundamental for current understanding the soil health status and for providing a comprehensive assessment of sustainable land management practices and conservation efforts. Recent advancements in molecular technologies, such as high-throughput sequencing, revealed the incredible diversity of soil microbiomes. On one hand, metagenomic sequencing allows the characterization of the entire genetic composition of soil microbiomes, and the examination of their functional potential and ecological roles; on the other hand, culturomics-based approaches and metabolic fingerprinting offer complementary information by providing snapshots of microbial diversity and metabolic activities both in and ex-situ. Long-term storage and cryopreservation of mixed culture and whole microbiome are crucial to maintain the originality of the sample in microbiome biobanking and for the development and application of microbiome-based innovation. This review aims to elucidate the available approaches to characterize diversity, function, and resilience of soil microbial communities and to develop microbiome-based solutions that can pave the way for harnessing nature’s untapped resources to cultivate crops in healthy soils, to enhance plant resilience to abiotic and biotic stresses, and to shape thriving ecosystems unlocking the potential of soil microbiomes is key to sustainable agriculture. Improving management practices by incorporating beneficial microbial consortia, and promoting resilience to climate change by facilitating adaptive strategies with respect to environmental conditions are the global challenges of the future to address the issues of climate change, land degradation and food security. Copyright © 2024 Clagnan, Costanzo, Visca, Di Gregorio, Tabacchioni, Colantoni, Sevi, Sbarra, Bindo, Nolfi, Magarelli, Trupo, Ambrico and Bevivino.

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