Interest in the physiologic and pathologic effects of ROS on male fertility is growing. The controlled generation of very low amounts of ROS seems to regulate the acquisition of sperm-fertilizing ability. High levels of ROS endanger sperm function and viability. Oxidative stress can arise as a consequence of excessive production of ROS or impaired antioxidant defense mechanisms in semen. Oxidative stress precipitates a range of pathologies that are thought to affect the male reproductive system. ROS-mediated peroxidative damage to the sperm plasma membrane may account for the defective sperm functions observed in a high proportion of infertility patients. High levels of ROS in semen have been correlated with reduced sperm motility and damage to sperm nuclear DNA. Determining the levels and the sources of excessive ROS production in human semen and precise evaluation of the scavenger system may be useful tools to develop therapeutic strategies for male infertility. Therapeutic interventions directed toward the isolation of mature spermatozoa by in vitro separation techniques may benefit infertile men in whom oxidative stress has a significant role. Nevertheless, this approach may be limited by the fact that the prolonged centrifugation involved in these procedures may enhance ROS production by spermatozoa. Clinical trials using antioxidants in vivo and in vitro have resulted in a major debate, and further research is required before one can be optimistic about a role for antioxidants in the treatment of infertile men. A double-blind, placebo-controlled study underway at the authors' center is evaluating the effects of treating infertile men with a combination of vitamins E and C after adjusting for all causes of controversy.