Linkage studies previously mapped a prostate cancer susceptibility locus to a 15.5-Mb region on chromosome 17. Kathleen Cooney and colleagues now show that a rare, nonsynonymous variant in HOXB13 located in the linkage interval is associated with substantially elevated risk of the disease (N. Engl. J. Med. 366, 141–149, 2012). The authors sequenced 202 genes from the linkage region in 94 families with prostate cancer and identified 4 families carrying the same nonsynonymous variant in HOXB13. Follow-up studies in 5,083 prostate cancer cases and 1,401 controls of European ancestry showed that this variant was enriched in cases (1.4%) compared to controls (0.1%) and was associated with a 20-fold higher risk of prostate cancer (P = 8.5 × 10−7). The authors found additional nonsynonymous HOXB13 variants in two other families with prostate cancer and in two prostate cancer cell lines. HOXB13 is expressed in the developing and adult prostate and has previously been implicated in prostate cancer biology. The disease-associated variants map to conserved domains important for protein-protein interactions and DNA-binding activity and may increase prostate cancer risk through a gain-of-function mechanism.