An intensive agricultural production is necessary to satisfy food requirements for the growing world population. However, its realization is associated with the mass consumption of non-renewable natural resources and with the emission of greenhouse gases causing climate changes. The research challenge is to meet sustainable environmental and economical issues without compromising yields. In this context, exploiting the agroecosystem services of soil microbial communities appears as a promising effective approach. This chapter reviews the research efforts aimed at improving a sustainable and healthy agricultural production through the appropriate management of soil microorganisms. First, the plant-associated microbiome is briefly described. Then, the current research technologies for formulation and application of inocula based on specific beneficial plant-associated microbes are summarized. Finally, the perspectives and opportunities to manage naturally existing microbial populations, including those non-culturable, are analyzed. This analysis concerns: (i) a description of the already available, culture-independent, molecular techniques addressed at increasing our understanding of root-microbiome interactions; (ii) how to improve the ability of soil microbes for alleviating the negative impacts of stress factors on crop productivity; and (iii) whether plants can structure their rootassociated microbial communities and, leading on from this, whether the rhizosphere can be engineered (biased) to encourage beneficial organisms, while prevent presence of pathogens.