Infertility has become a critical health burden, with an estimated 80 million individuals experiencing the weight of this disease globally. At least 50% of infertile cases in Australia involve a male factor, making defective sperm function one of the largest, defined causes of human infertility. Unfortunately, due to a lack of mechanistic knowledge surrounding sperm function, there are few molecular tools available for the accurate diagnosis of male infertility and no successful preventative strategies. This is particularly concerning as there is now compelling evidence that poor sperm quality may be prescient of major systemic diseases such as cardiovascular disease, diabetes, and cancer. It is well established that germline oxidative stress is responsible for a large proportion of male infertility cases. Through comparative proteomic analyses targeted at understanding the induction of oxidative stress, we have recently reported on a novel enzyme responsible for its catalysis termed 15-arachidonate lipoxygenase (ALOX15). In somatic cells, the overproduction of damaging lipid peroxidation products such as 4-hydroxynonenal (4HNE) is primarily attributed to the action of lipoxygenase enzymes, which facilitate the oxygenation and degradation of polyunsaturated fatty acids. Our recent work has provided the first evidence for the mediation of oxidative stress by ALOX15 in the male germline and accordingly, cellular reactive oxygen species and lipid peroxidation events can be prevented through the selective inhibition of ALOX15 with 6,11-dihydro  benzothiopyrano [4,3-b] indole (PD146176). This, in turn, ameliorates changes to germ cell protein homeostasis that are commonly elicited by 4HNE and results in a recovery of human sperm-egg interaction under conditions of oxidative stress. Combined, our data establish ALOX15 as a key physiological target to prevent oxidative stress-mediated pathologies in both the developing sperm cells of the testis and in mature human spermatozoa.