Purpose: To identify the RP3 gene responsible for the major form of X-linked retinitis pigmentosa (XLRP). Methods: Positional cloning strategy is being employed to identify the RP3 gene. The genomic region of ≈500 kb spanning the RP3 gene has been isolated in YAC, cosmid and phage clones. Several methods are being used to identify transcribed sequences from the cloned RP3 critical region; these include exon-amplification, cDNA selection using filter-hybridization and magnetic capture, direct screening of retinal cDNA libraries with whole cosmid probes, and a novel sandwich-selection method. Results: A total of about 200 clones isolated by different methods are being characterized. So far, we have identified at least five novel sequences by exon-amplification, four clones by cDNA selection, seven clones by direct screening and one cDNA clone by sandwich-selection. All of the putative transcribed sequences are being analyzed further by mapping to the RP3 critical region and by Northern analysis of retinal RNA. We have also initiated the search of gross DNA alterations and single base pair changes in RP3 patients using several of the better-characterized clones from the region. Conclusions: We have isolated a large number of putative transcribed sequences from the RP3 region and are searching for mutations in RP3 patients.