According to the United Nations, there are over 200 million pregnancies around the world each year and 121 million of these are unintended. While present contraceptive methods are effective, there is clearly a need to develop additional methods of contraception for males, a market which is clearly lacking. Therapeutic targets for male contraception are associated with numerous problems due to their focus on disrupting spermatogenesis or hormonal mechanisms to produce dysfunctional sperm. We have described a mechanism for male contraception that is both non-hormonal and non-spermatogenic. This biological strategy has been validated via the dual genetic deletion of α1A-adrenergic receptors and P2X1-purinergic receptors in male mice thereby blocking sympathetically mediated sperm transport through the vas deferens during the emission phase of ejaculation. This modification produced 100% infertility without effects on sexual behaviour or function. Sperm taken from the cauda epididymides of double knockout mice were microscopically normal and motile. Furthermore, double knockout sperm were capable of producing normal offspring following intracytoplasmic sperm injection into wild type ova and implantation of the fertilized eggs into foster mothers. Blood pressure and baroreflex function was reduced in double knockout mice but no more than single knockout of α1A-adrenergic receptors alone. These results suggest that this autonomic method of male contraception appears free from major physiological and behavioural side effects. In addition, they provide conclusive proof of concept that pharmacological antagonism of the P2X1-purinergic receptor and α1A-adrenergic receptor provides a safe and effective therapeutic target for a non-hormonal, readily reversible male contraceptive. Synthetic medicinal chemistry approaches to discover a suitable P2X1-purinergic receptor antagonist to use in combination with tamsulosin for this purpose has so far proved unsuccessful. However, our recent determination of the first cryo-EM structure for the P2X1 receptor will hopefully provide better chemical starting points for a successful synthetic medicinal chemistry program.