Familial clustering of early-onset prostate cancer best fits a model of autosomal dominant inheritance of a rare, high-risk allele, predisposing 9% of all prostate cancer occurrences. Prostate cancer is inherited in a Mendelian fashion in these families, providing an opportunity to apply linkage or association analysis to this complex disease. We have developed and applied high-throughput fluorescent methods to enable genotyping of hundreds of individuals from affected families at high density, followed by high marker resolution analysis. Allele identification is accomplished in a semi-automated fashion; with genome surveys completed with both parametric and non-parametric methods of analysis employed. Results provided evidence of the first locus for hereditary prostate cancer (termed HPC1), and subsequently on a second locus for a susceptibility gene in human prostate cancer on the X-chromosome (termed HPC-X). Supplemental pedigrees are now also being genotyped in the higher density survey to increase power to refine linkage for these and other candidate loci. We continue to collect extended pedigrees with prostate cancer in Finland, Iceland and Sweden as confirmatory populations. Physical mapping to identify the HPC1and HPCX genes are a primary function of this program. Further study is necessary and results will be reported in the future.