Comprehensive understanding of functional elements in the human genome will require thorough interrogation and comparison of individual human genomes and genomic structures. Such an endeavor will require improvements in the throughputs and costs of DNA sequencing. Next-generation sequencing platforms have impressively low costs and high throughputs but are limited by short read lengths. An immediate and widely recognized solution to this critical limitation is the paired-end tag (PET) sequencing for various applications, collectively called the PET sequencing strategy, in which short and paired tags are extracted from the ends of long DNA fragments for ultra-high-throughput sequencing. The PET sequences can be accurately mapped to the reference genome, thus demarcating the genomic boundaries of PETrepresented DNA fragments and revealing the identities of the target DNA elements. PET protocols have been developed for the analyses of transcriptomes, transcription factor binding sites, epigenetic sites such as histone modification sites, and genome structures. The exclusive advantage of the PET technology is its ability to uncover linkages between the two ends of DNA fragments. Using this unique feature, unconventional fusion transcripts, genome structural variations, and even molecular interactions between distant genomic elements can be unraveled by PET analysis. Extensive use of PET data could lead to efficient assembly of individual human genomes, transcriptomes, and interactomes, enabling new biological and clinical insights. With its versatile and powerful nature for DNA analysis, the PET sequencing strategy has a bright future ahead.Genomics holds much promise for huge improvements in human healthcare. However, genomics faces several practical challenges. Human genomes are read out as linear sequences, but in the cell, there are many complex interactions and mechanisms that operate around human DNA to transduce DNA information into biological function (The ENCODE Project Consortium 2007). Conventional DNA sequencing has been used to extensively explore genetic elements and structures; however, high sequencing costs and low throughputs have historically limited in-depth analysis of a broad range of genomic elements, making the development of new sequencing strategies necessary.Next-generation sequencing technologies are transforming the field of genomic science (Schuster 2008). The currently available next-generation sequencing methods (Margulies et al. 2005;Shendure et al. 2005;Barski et al. 2007;Johnson et al. 2007) read DNA templates in a highly parallel manner to generate massive amounts of sequencing data, but the read length for each DNA template is short compared with that of traditionally used Sanger capillary sequencing instruments. This massively parallel and short read strategy of DNA sequencing opens many new ways for interrogating human genomes (Wold and Myers 2008). However, the short read lengths lead to serious limitations in applying this enormous sequencing power to many biological applicati...