An estimated 10 to 15% of couples suffer from infertility, and many treatment decisions rely on trial and error. In this issue of Science Translational Medicine, Tollner and colleagues provide strong evidence from a human genetics study that a common variant in the beta defensin 126 gene, the "del" variant, can reduce male fertility substantially. In addition, they show a plausible mechanism for reduced fertility: Sperm from del/del homozygotes lack an important component of their glycoprotein coat and have difficulty penetrating a surrogate for cervical mucus. If replicated in future studies, these findings promise to guide choices about the timing and type of assisted reproduction interventions-and further hint at the possibility of treating sperm from del/del homozygotes to promote fertility.