Plant evolution is largely driven by plant–microbe interactions, yet the ecology of the plant holobiont is not well understood at a molecular level. However, these relationships hold diverse benefits for sustainable agriculture as nature-based solutions (NbS). We propose a workflow to enhance understanding of natural variation in the plant–soil microbiome holobiont, addressing key challenges like growth promotion, stress resilience, nitrogen use efficiency (NUE), biological nitrification inhibition (BNI), healthy soils, and improving fertilization practices towards a more natural agroecosystem. We discuss a panome-wide association study (PWAS) approach to discover and incorporate novel genetic diversity from exotic germplasm into breeding populations. Ultimately, understanding natural variation of the holobiont in agroecosystems will contribute to the development of novel climate-resilient crop varieties for food security.