The development of reliable methods for annotation of clinical phenotypes and algorithms to calculate similarity values for clinical phenotype profiles will be a major challenge for genomic personalized medicine, since combined analysis of phenotypic features and genetic variants can increase diagnostic yield, especially with exome or genome sequencing. The Human Phenotype Ontology project (HPO;) provides an ontology for capturing phenotypic abnormalities in human disease in a precise and comprehensive fashion. The HPO not only enables reliable integration of disease-relevant information from numerous databases, but it also allows for similarity between patients or between patients and disease descriptions to be calculated algorithmically. The HPO thereby represents a solid foundation for differential diagnostic applications as well as for translational research and prioritization of novel disease genes in exome or genome sequencing projects.