All sperm accrue varying amounts of DNA damage during maturation and storage, a process that appears to be mediated through oxidative stress. The clinical significance of genetic damage in the male germ line depends upon severity and how that damage is distributed among the sperm population. In human reproduction, the embryo is capable of significant DNA repair, which occurs prior to the first cleavage event. However, when the magnitude of genomic damage reaches pathologic levels, reproductive outcomes begin to be affected. Evidence now exists linking excessive sperm DNA fragmentation with time to pregnancy for natural conception, pregnancy outcomes of intrauterine insemination and in vitro fertilization, and miscarriage rates when intracytoplasmic sperm injection is employed. This review will discuss the pathophysiology of sperm DNA damage, the studies linking it to impaired reproductive outcomes, and how clinicians may render treatment to optimize the chance of paternity for their patients.