Genetic and molecular studies of inborn disorders of the immune system (primary immunodeficiencies, PIDs) have immensely enhanced our understanding of the core components involved in human immunity. The majority of PIDs follow Mendelian inheritance, thus offering relatively clear genotype-phenotype relationships. Of particular importance, affected cells can be obtained with relative ease, enabling dissection of underlying pathomechanisms and molecular interventions to normalize cellular and biochemical phenotypes. We here propose to use PIDs as model diseases to rationalize patient-specific workflows from gene discovery and pathomechanisms to targeted treatment, rendering these disorders paradigmatic models to establish principles of molecular-guided, stratified treatment. Moving beyond individual lab efforts, we will establish an integrative workflow of high-throughput sequencing, high-content imaging, proteomics, genome editing and network biology, in order to: (i) prioritize genetic variants for their potential to be disease-causing ; (ii) characterize in depth the pathomechanisms associated to novel PID entities ; (iii) rationalize patient-specific small molecule drug screening to identify targeted therapies. Collectively, our consortium will identify and characterize novel disorders of the human immune system and provide proof-of-concept for the combined use of functional genomics, network biology and drug screening approaches to identify personalized treatment options.