the members of the DOE and NIH planning groups R E V I E W The Human Genome Project has successfully completed all the major goals in its current 5-year plan, covering the period 1993-98. A new plan, for 1998 -2003, is presented, in which human DNA sequencing will be the major emphasis. An ambitious schedule has been set to complete the full sequence by the end of 2003, 2 years ahead of previous projections. In the course of completing the sequence, a "working draft" of the human sequence will be produced by the end of 2001. The plan also includes goals for sequencing technology development; for studying human genome sequence variation; for developing technology for functional genomics; for completing the sequence of Caenorhabditis elegans and Drosophila melanogaster and starting the mouse genome; for studying the ethical, legal, and social implications of genome research; for bioinformatics and computational studies; and for training of genome scientists.The Human Genome Project (HGP) is fulfilling its promise as the single most important project in biology and the biomedical sciences-one that will permanently change biology and medicine. With the recent completion of the genome sequences of several microorganisms, including Escherichia coli and Saccharomyces cerevisiae, and the imminent completion of the sequence of the metazoan Caenorhabditis elegans, the door has opened wide on the era of whole genome science. The ability to analyze entire genomes is accelerating gene discovery and revolutionizing the breadth and depth of biological questions that can be addressed in model organisms. These exciting successes confirm the view that acquisition of a comprehensive, high-quality human genome sequence will have unprecedented impact and long-lasting value for basic biology, biomedical research, biotechnology, and health care. The transition to sequence-based biology will spur continued progress in understanding gene-environment interactions and in development of highly accurate DNA-based medical diagnostics and therapeutics.Human DNA sequencing, the flagship endeavor of the HGP, is entering its decisive phase. It will be the project's central focus during the next 5 years. While partial subsets of the DNA sequence, such as expressed sequence tags (ESTs), have proven enormously valuable, experience with simpler organisms confirms that there can be no substitute for the complete genome sequence. In order to move vigorously toward this goal, the crucial task ahead is building sustainable capacity for producing publicly available DNA sequence. The full and incisive use of the human sequence, including comparisons to other vertebrate genomes, will require further increases in sustainable capacity at high accuracy and lower costs. Thus, a high-priority commitment to develop and deploy new and improved sequencing technologies must also be made.Availability of the human genome sequence presents unique scientific opportunities, chief among them the study of natural genetic variation in humans. Genetic or DNA sequence variat...