Male infertility is a very common condition, with reports suggesting that one in 15-20 men of reproductive age are affected. Understanding why or how men produce defective sperm is a question that has remained elusive. We have used proteomic screens to identify mechanisms responsible for building defective sperm in men. Significantly, we have found regulators of alternate splicing appear to be a major key; being more abundant within infertile spermatozoa. To understand this, we overexpressed specific alternate-splicing regulators within Drosophilia. Amazingly, our data show that sperm overexpression RNA-splicing regulators produced typical patterns of “male-factor” infertility, including (i) decreased amounts of sperm production, (ii) head morphology defects and (iii) poor sperm motility. Furthermore, fertility data demonstrate changes to alternate splicing have dramatic consequence. Fly strains ranged from completely infertile to extremely subfertile. This data strongly suggest that aberrant alternate splicing is likely to play a major role when it comes to the production of poor quality spermatozoa, and male factor infertility.