Whole exome sequencing presents a powerful tool to study rare genetic disorders. The most challenging part of using exome sequencing for the purpose of disease-causing variant detection is analyzing, interpreting, and filtering the large number of detected variants. In this chapter we provide a comprehensive description of the various steps required for such an analysis. We address strategies in selecting samples to sequence, and technical considerations involved in exome sequencing. We then discuss how to identify variants, and methods for first annotating detected variants using characteristics such as allele frequency, location in the genome, and predicted severity, and then classifying and prioritizing the detected variants based on those annotations. Finally, we review possible gene annotations that may help to establish a relationship between genes carrying high-priority variants and the phenotype in question, in order to identify the most likely causative mutations.