Next-generation sequencing (NGS) is transforming clinical research and diagnostics, vastly enhancing our ability to identify novel disease-causing genetic mutations and perform comprehensive diagnostic testing in the clinic. Whole-exome sequencing (WES) is a commonly used method which captures the majority of coding regions of the genome for sequencing, as these regions contain the majority of disease-causing mutations. The clinical applications of WES are not limited to diagnosis; the technique can be employed to help determine an optimal therapeutic strategy for a patient considering their mutation profile. WES may also be used to predict a patient’s risk of developing a disease, e.g., type 2 diabetes (T2D), and can therefore be used to tailor advice for the patient about lifestyle choices that could mitigate those risks. Thus, genome sequencing strategies, such as WES, underpin the emerging field of personalized medicine. Initiatives also exist for sharing WES data in public repositories, e.g., the Exome Aggregation Consortium (ExAC) database. In time, by mining these valuable data resources, we will acquire a better understanding of the roles of both single rare mutations and specific combinations of common mutations (mutation signatures) in the pathology of complex diseases such as diabetes. Herein, we describe a protocol for performing WES on genomic DNA extracted from blood or saliva. Starting with gDNA extraction, we document preparation of a library for sequencing on Illumina instruments and the enrichment of the protein-coding regions from the library using the Roche NimbleGen SeqCap EZ Exome v3 kit; a solution-based capture method. We include details of how to efficiently purify the products of each step using the AMPure XP System and describe how to use qPCR to test the efficiency of capture, and thus determine finished library quality.