In nature, plants live in complex environments in which they are attacked by a multitude of pathogens and pests. In agriculture this leads to tremendous annual crop losses, representing a value of over 450 billion worldwide. Beneficial associations between plants and other organisms are abundant in nature as well, improving plant growth or aiding plants to overcome biotic or abiotic stress. In the past years, we pioneered research on the complexity of the natural plant immune system that is engaged in interactions of plants with beneficial microbes, pathogens and insect herbivores. We discovered that the plant immune signaling network finely balances the plant¿s response to beneficial and harmful organisms to maximize both profitable and protective functions. As plants have co-evolved with an enormous variety of alien organisms, they harbour a fantastic reservoir of natural defensive mechanisms that until to date remained largely untapped. Here, I propose to mine this undiscovered natural resource in detail, using the Arabidopsis thaliana model system, and an innovative multidisciplinary approach involving a unique combination of state-of-the-art microbial and plant functional genomics, ecogenomics, molecular genetics, cellular biology, computational biology and bioinformatics. The outcomes of the proposed project will provide a detailed understanding of the intrinsic capacity of the plant immune system to simultaneously accommodate mutualists and ward off enemies in order to maximize benefits and minimize damage. Profitably, the discovery of novel plant loci and mechanisms involved in plant immunity will provide multi-faceted possibilities for development of new strategies for sustainable agriculture and resistance breeding of economically relevant crop species.