Recent scientific discoveries fuelled by the application of next-generation DNA and RNA sequencing technologies highlight the striking impact of these platforms in characterizing multiple aspects in genomics research. This technology has been used in the study of the B-cell and T-cell receptor repertoire. The novelty of immunosequencing comes from the recent rapid development of techniques and the exponential reduction in cost of sequencing. Here, we describe some of the technologies, which we collectively refer to as Rep-Seq (repertoire sequencing), to portray achievements in the field and to present the essential and inseparable role of next-generation sequencing to the understanding of entities in immune response. The large Rep-Seq data sets that should be available in the near future call for new computational algorithms to segue the transition from ‘classic’ molecular-based analysis to system-wide analysis. The combination of new algorithms with high-throughput data will form the basis for possible new clinical implications in personalized medicine and deeper understanding of immune behaviour and immune response.