Antimicrobial peptides provide a defense system against microorganisms. One class of these molecules binds lipophilic substrates and is therefore directed against gram-negative bacteria. This family includes proteins related to bactericidal/permeability-increasing protein (BPI). We characterized an approximately 100-kb cluster of three human genes named RYSR, RYA3, and RY2G5 that are related to the BPI family. The RY cluster maps to 20q11.21, >5 Mb upstream of the BPI cluster. The RY and BPI genes have similar exon structures, indicating that they were derived by duplication from a common ancestor. We identified mouse BPI-related and RY orthologues in syntenic regions, indicating that the gene family expanded before mouse and human diverged. Expression analyses show that RYs are strongly expressed in the olfactory epithelium, suggesting that they also could act as odorant transporters or detoxification agents in the olfactory system. Together, these data show how mammals diversified their antimicrobial defenses/olfactory pathways through a duplication-driven adaptive selection process.