In medical contexts, the word “phenotype” is used to refer to some deviation from normal morphology, physiology, or behavior. The analysis of phenotype plays a key role in clinical practice and medical research, and yet phenotypic descriptions in clinical notes and medical publications are often imprecise. Deep phenotyping can be defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The emerging field of precision medicine aims to provide the best available care for each patient based on stratification into disease subclasses with a common biological basis of disease. The comprehensive discovery of such subclasses, as well as the translation of this knowledge into clinical care, will depend critically upon computational resources to capture, store, and exchange phenotypic data, and upon sophisticated algorithms to integrate it with genomic variation, omics profiles, and other clinical information. This special issue of Human Mutation offers a number of articles describing computational solutions for current challenges in deep phenotyping, including semantic and technical standards for phenotype and disease data, digital imaging for facial phenotype analysis, model organism phenotypes, and databases for correlating phenotypes with genomic variation. Hum Mutat 33:777–780, 2012. © 2012 Wiley Periodicals, Inc.