Root exudates, species-specific metabolites released by plants into the rhizosphere, shape plant nutrient uptake, plant–plant and plant–microbiome interactions. When optimized, such interactions boost the productivity of sustainable agricultural systems such as intercropping and crop rotation. However, why certain combinations of crops are beneficial and others are not, remains unclear. This Essay outlines how optimal crop combinations could be determined, focusing on the molecular interplay of crops and their microbial partners. With an advanced understanding of root exudation and its effects on microbes, new strategies for sustainable farming could be unlocked, reducing reliance on fertilizers and pesticides, and tackling challenges raised by a changing climate.