In this review, we will outline our current understanding of how sperm DNA is organized, what causes sperm DNA damage, what impact this damage may have on reproductive capacity and whether tests of sperm DNA damage are clinically useful.Inter and intramolecular disulfide crosslinks between the cysteinerich protamines are responsible for the compaction and stabilization of the sperm nucleus.It is thought that this nuclear compaction is important to protect the sperm genome from external stresses such as oxidation or temperature elevation.The current understanding is that sperm chromatin is tightly packaged by protamines, but up to of the DNA remains packaged by histones at specific DNA sequences. The histonebound DNA sequences are less tightly compacted, and it is thought that these DNA sequences or genes may be involved in fertilization and early embryo development.The retained histones are associated with the nuclear periphery and with telomeres. The sperm mitochondrial DNA is a small, circular DNA that is not bound to proteins.Mitochondrial DNA exhibits a high rate of mutation.Sperm motility is related to the mitochondrial volume within the sperm midpiece, and mutations or deletions in the mitochondrial DNA have been associated with reduced sperm motility.Although inheritance of mitochondrial DNA is primarily maternal, paternal transmission of mitochondrial DNA mutations have been reported. The examination of mitochondrial DNA may gain some importance in the evaluation of male infertility, particularly in relation to assisted reproductive technologies.A single case report indicated that a febrile illness can cause a transient increase in the nuclear histone: protamine ratio and associated abnormalities of sperm chromatin structure.This association between sperm DNA damage and protamine deficiency suggests that the damage may be due to a defect in spermiogenesis. Sperm DNA damage has been associated with high levels of reactive oxygen species, high levels of which have been detected in the semen of of infertile men.Although low levels of reactive oxygen species are necessary for normal sperm function, high levels are generated by defective spermatozoa and by semen leukocytes, which results in sperm dysfunction.The association between sperm DNA damage and spermderived reactive oxygen species suggests that DNA damage may be caused by a defect in spermiogenesis, whereas the association between sperm DNA damage and leukocytederived reactive oxygen species suggests that the DNA damage may be caused by a posttesticular defect.The sperm midpiece represents the proximal part of the sperm tail and is rich in mitochondria.Although there is not much clinical evidence, most clinicians will counsel patients to delay parenthood until months after cancer treatment.Patients who are scheduled to undergo definitive cancer therapy are strongly encouraged to have their sperm preserved for future use.Varicoceles have been associated with sperm DNA damage.The level of sperm DNA damage is related to the high levels of oxidative stress found in the semen of infertile men with this condition.Compared with wildtype mice, follicestimulatinghormonereceptor knockout mice have been found to have lower levels of sperm nuclear protamines and lower testosterone, impaired fertility and higher levels of DNA damage.It is suggested that smoking causes increased production of leukocy teder ived reactive oxygen spec ies, wh ich has adverse effects on mature sperm.