Agriculture faces unprecedented challenges due to climate change, increasing food demand, and resource scarcity, which needs sustainable and innovative solutions. This review explores the emerging paradigm of holobiont biology (host and its microbiome as biological unit) in the context of emerging plant health challenges driven by global changes. We highlight three critical challenges: the rise of complex plant syndromes, the emergence and re-emergence of plant diseases, and the consequences of dysbiotic plant microbiomes. We discuss how microbiome-based strategies can enhance plant resilience, reduce reliance on agrochemicals, and foster sustainable agriculture. Integrating these strategies with advanced frameworks, such as holo-omics and machine learning, opens avenues for microbiome-based solutions to address agricultural challenges in the era of global changes, ensuring resilient crop systems and planetary health.

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