Chromosome 21 represents approximately 1% of the human genome, and its long arm has been estimated to contain 600-1000 genes. A dense linkage map and almost complete physical maps based on yeast artificial chromosomes (YACs) and cosmids have been developed. We have used exon trapping to identify portions of genes from randomly picked chromosome 21-specific cosmids, to contribute to the creation of the transcription (genic) map of this chromosome and the cloning of its genes. A total of 559 different sequences were identified after elimination of false-positive clones and repetitive elements. Among these, exons for 13 of the 30 known chromosome 21 genes have been "trapped." In addition, a considerable number of trapped sequences showed homologies to genes from other species and to human expressed sequence tags (ESTs). One hundred thirty-three trapped sequences were mapped, and every one mapped back to chromosome 21. We estimate that we have identified portions of up to approximately 40% of all genes on chromosome 21. The genic map of chromosome 21 provides a valuable tool for the elucidation of function of the genes and will enhance our understanding of the pathophysiology of Down syndrome and other disorders of chromosome 21 genes.