Agricultural production faces different environmental challenges and the attack of pathogens that can lead to serious economic losses. Traditionally, to avoid a reduction in production, agrochemicals have been applied that increase crop nutrition and eliminate pathogen infections; however, the collateral damage of these synthetic chemicals in human and animal health, as well as environmental contamination, make us reflect on implementing new strategies with a more sustainable perspective. Such is the case of the use of beneficial microorganisms (and their genomic reservoir) associated with plants, which is known as the microbiome. The microbiome can interact from different plant zones and influence metabolism, physiology, as well as genetic responses that modulate an improved plant phenotype that can tolerate different types of abiotic and biotic stresses. In recent years, different strategies have been integrated for the engineering of the plant microbiome, observing encouraging results that are allowing to continue supplying the global food demand in a sustainable way. In this Topical Collection on "The role of plant microbiome engineering in stressful agriculture", we invite colleagues to submit research and review works that share new results on the subject, as well as establish a discussion about the benefits of modifying the plant microbiome to face the challenges of future in agriculture, and particularly that which is subjected to different stress conditions.