New technology in molecular biology and quantitative analysis has led to an explosion of the knowledge and understanding of inherited diseases. Efforts to map the entire human genome have progressed further than had been expected. Gene therapy is being investigated for possible use in the treatment of a host of diseases, ranging from cystic fibrosis to cancer. Diagnosis before the development of symptoms is possible for people at risk for some diseases with a delayed onset, such as Huntington disease, Alzheimer disease, and familial breast cancer. Advances in analytical and molecular tools in the 1980's made it feasible, for the first time, to begin sequencing the three billion nucleotides of DNA that make up the human genome. The Human Genome Project, an international effort, was initiated under the auspices of the human gene-mapping conferences and was formalized through the Human Genome Organization (HUGO). In the United States, the efforts have been jointly funded and coordinated by the National Institutes of Health and the Department of Energy since 1990, although private organizations also have played a prominent role. In addition to supporting scientific inquiry, the National Institutes of Health and the Department of Energy have allocated approximately 5 per cent of their funding for the human genome project for the study of the ethical, legal, and social issues relating to that project. In the first five years in which funding was provided, substantial progress was made toward an initial set of primary goals28 that included the development of highresolution genetic maps73 , improvements in analytical strategies51 , and tremendous increases in the numbers of available polymorphic markers, physical mapping reagents, and mapped genes. At the present time, genetic maps composed of markers that are easy to use, inexpensive, and efficient (that is, those that are based on a polymerase chain reaction) make it practical for even groups of a few individuals to map genes in only a few *No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. No funds were received in support of this study. tDepartments of Orthopaedic Surgery (F. R. D.) and Pediatrics (K. D. M.), University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, Iowa 52242. years. This is in contrast to the hundreds of personyears that were required for earlier successful searches, such as those that resulted in the discovery of the causative gene for cystic fibrosis. Similarly, advances in analysis allow the practical study of even complex disorders such as clubfoot or scoliosis. Because of the tremendous strides in physical mapping, once a gene is localized by this means the gene itself may be more quickly identified. There is now an emphasis on finding and mapping of all of the approximately 80,000 human genes along with mouse homologs. An effort to complete the full human DNA sequence has recently been initiated and is likely to be completed in the next fifteen years. In the last five years alone, the number of polymorphisms has increased from 2000 to 15,000; the number of mapped genes, from 1500 to more than 8000; and the amount of DNA sequenced in humans, from five million to more than fifty million base pairs. The causative genes for many conditions, including skeletal dysplasias (achondroplasia, multiple epiphyseal dysplasia, pseudoachondroplasia, spondyloepiphyseal dysplasia, diastrophic dysplasia, metaphyseal chondrodysplasia, and precocious osteoarthrosis), connectivetissue disorders (Marfan syndrome and Ehlers-Danlos syndrome), metabolic diseases (osteoporosis, osteopetrosis, and hypophosphatemic rickets,), muscular dystrophies (Duchenne and Becker dystrophy, limb-girdle dystrophy, facioscapulohumeral dystrophy, and myotonic dystrophy), peripheral neuropathies (CharcotMarie-Tooth disease), and syndromes with orthopaedic manifestations (McCune-Albright polyostotic fibrous dysplasia, Apert syndrome, and distal arthrogryposis) have been identified or localized by investigators. The mechanisms by which mutations in the disease-causing genes result in the disease phenotype are being actively investigated. These investigations are producing new information concerning the biology of normal and abnormal growth and development and tissue function at the molecular level.