Classical soil science approaches have enabled us to establish basic principles of how the soil system functions and have answered numerous practical agricultural application questions. In recent years, efforts have been refocused on better understanding, managing and benefiting from this system that contains one of the most complex biological communities of the planet. Soil biology is seen as being at the center of scientific research of this century, with novel research objectives and goals being set. In addition, plant nutrition has enabled us to understand nutrient uptake, transport and mobilization mechanisms in plants, and both disciplines have converged on the area of microorganism-mediated plant nutrition. The challenge for these scientific areas is to identify microorganism communities and the roles they play in their habitats, as well as the mechanisms that plants have to make better use of nutrients. Genomics and metagenomics, along with microbiological techniques, are contributing greatly to advances in our understanding of living systems that exist in the soil and their interaction with plants. For its part, molecular plant nutrition has made significant progress in understanding the use of nutrients by plant cells, and has identified molecular mechanisms that can improve nutrient use efficiency. Together, molecular soil microbiology and molecular plant nutrition are projected to be a driving force in agriculture and sustainable food production in the coming years. Herewith, we aim to integrate recent literature on basic and applied research concerning plant and microbe genomics in terms of their potential for developing a novel molecular plant nutrition approach, with special emphasis on nitrogen, potassium and phosphorous as the major macronutrients for crop plants.