Interrogation of tissue informs on patient management through delivery of a diagnosis together with associated clinically relevant data. The diagnostic pathologist will usually evaluate the morphological appearances of a tissue sample and, occasionally, the pattern of expression of a limited number of biomarkers. Recent developments in sequencing technology mean that DNA and RNA from tissue samples can now be interrogated in great detail. These new technologies, collectively known as next-generation sequencing (NGS), generate huge amounts of data which can be used to support patient management. In order to maximize the utility of tissue interrogation, the molecular data need to be interpreted and integrated with the morphological data. However, in order to interpret the molecular data, the pathologist must understand the utility and the limitations of NGS data. In this review, the principles behind NGS technologies are described. In addition, the caveats in the interpretation of the data are discussed, and a scheme is presented to “classify” the types of data which are generated. Finally, a glossary of new terminology is included to help pathologists become familiar with the lexicon of NGS-derived molecular data.