Male infertility is a global problem and the number of men suffering from this condition has increased dramatically over the last decade. Currently, approximately 10–15% of couples have been affected by this worldwide. Although this is a crucial problem, treatment options are limited and sometimes even ineffective. In order to arrest this worrisome increase, the development of new treatment strategies has become fundamental. Redox regulation driven by NO in reproductive biology represents a novel pathway in male infertility and it plays a crucial role in maintaining normal fertilisation capacity. Compelling evidence states that ROS synthesis and degradation should be in perfect balance and tightly regulated by endogenous and exogenous antioxidant enzymes. NO donor drugs might play a beneficial role in restoring this fragile equilibrium and have shown great potential in ameliorating overall fertilisation capacity.