Despite its apparently simple genetics,cystic fibrosis(CF) is a rather complex genetic disease.A lot of variability in the steps of the path from the cystic fibrosis transmembrane conductance regulator(CFTR) gene to the clinical manifestations originates an uncertain genotype- phenotype relationship.A major determinant of this uncertainty is the incomplete knowledge of the CFTR mutated genotypes,due to the high number of CFTR mutations and to the higher number of their combinations in trans and in cis.Also the very limited knowledge of functional effects of CFTR mutated alleles severely impairs our diagnostic and prognostic ability.The final phenotypic modulation exerted by CFTR modifier genes and interactome further complicates the framework.The next generation sequencing approach is a rapid,lowcost and high-throughput tool that allows a near complete structural characterization of CFTR mutated genotypes,as well as of genotypes of several other genes cooperating to the final CF clinical manifestations.This powerful method perfectly complements the new personalized therapeutic approach for CF.Drugs active on specific CFTR mutational classes are already available for CF patients or are in phase 3 trials.A complete genetic characterization has been becoming crucial for a correct personalized therapy.However,the need of a functional classification of each CFTR mutation potently arises.Future big efforts towards an ever more detailed knowledge of both structural and functional CFTR defects,coupled to parallel personalized therapeutic interventions decisive for CF cure can be foreseen. Despite its apparently simple genetics, cystic fibrosis (CF) is a rather complex genetic disease. A lot of variability in the steps of the path from the cystic fibrosis transmembrane conductance regulator (CFTR) gene to the clinical manifestations originates an uncertain genotype- phenotype relationship .A major determinant of this uncertainty is the incomplete knowledge of the CFTR mutated genotypes, due to the high number of CFTR mutations and to the higher number of their combinations in trans and in cis. Also the very limited knowledge of functional effects of CFTR mutated alleles severely impairs our diagnostic and prognostic ability. The final phenotypic modulation exerted by CFTR modifier genes and interactome further complicates the framework. next generation sequencing approach is a rapid, low cost and high-throughput tool that allows a near complete structural characterization of CFTR mutated genotypes, as well as of genotypes of several other genes cooperating to the final CF clinic al manifestations. This powerful method perfectly complements the new personalized therapeutic approach for CF. Drug active on specific CFTR mutational classes are already available for CF patients or are in phase 3 trials. A complete genetic characterization has been for crucial crucial for a correct personalized therapy. However, the need of a functional classification of each CFTR mutation potently arises. Future big efforts towards an ever more detailed knowledge of both structural and functional CFTR defects, coupled to parallel personalized therapeutic interventions decisive for CF cure can be foreseen.