Infertility is a major worldwide health burden, with 1 in 6 Australian couples taking recourse to assisted reproductive technologies. While the reasons for this concerning level of infertility are undeniably complex, a male factor is implicated in approximately 50% of these cases. In a vast majority of infertile males patients, sufficient numbers of spermatozoa are produced to achieve fertilization. However, the functionality of these cells has become compromised, thus ranking defective sperm function among the largest single defined cause of human infertility. The major aim of my laboratory is to understand the underlying molecular mechanisms responsible for sperm dysfunction in order to improve the clinical assessment and management of male infertility patients. In work conducted over the past two decades, we have studied the underlying pathophysiology of sperm dysfunction using a range of contemporary proteomic, molecular and cell biology technologies. A focus for this work has been defective sperm-oocyte recognition, a relatively common aetiology associated with the spermatozoa of idiopathic male infertility patients. Here, I will present our research into the functional maturation of the spermatozoon that underpins sperm-egg recognition and the mechanisms by which this process becomes so severely compromised in cases of infertility. I will also discuss our investigation of promising therapeutic interventions to mitigate the growing health burden posed by male infertility.