Oxygen toxicity is an inherent challenge to aerobic life, including spermatozoa, the cells responsible for propagation of the species. How this toxicity affects the spermatozoan in its interactions with the ovum is still unknown. An increase in oxidative damage to sperm membranes, proteins, and DNA is associated with alterations in signal transduction mechanisms that affect fertility. Recent evidence suggests that spermatozoa and oocytes possess an inherent but limited capacity to generate ROS to aid in the fertilization process. Though a variety of defense mechanisms encompassing antioxidant enzymes (SOD, catalase, and GSH peroxidase and reductase), vitamins (E, C, and carotenoids), and biomolecules (GSH and ubiquinol) are available, a balance of the benefits and risks from ROS and antioxidants appears to be necessary for the survival and functioning of spermatozoa. An assay system for the evaluation of OSS needs to be developed. Such an assay will assist the clinician in the assessment of fertility status of both male and female partners. The determination of this OSS value will also theoretically identify the subgroups of responders and nonresponders to any putative antioxidant therapy. Though the therapeutic use of antioxidants appears attractive, clinicians need to be aware of exaggerated claims of antioxidant benefits by various commercial supplements for fertility purposes until proper multicenter clinical trial have been completed.