Despite considerable effort and characterization, the precise role of PKA in regulating sperm development and the acquisition of motility and fertilization competence remains unclear. A major roadblock in these studies has been the lack of techniques to manipulate the expression and activity of PKA in sperm cells since no readily accessible cell culture model is available that allows genetic intervention. Specifically, my studies have used mouse genetics to introduce null mutations in specific subunits of PKA in male mice whose fertility and sperm function were then examined. To date we have learned the following: 1) although the type II regulatory subunit alpha (RII alpha) was previously thought to be critical for localizing PKA to the sperm flagellum and playing a key role in sperm motility, we demonstrated that RII alpha is not essential for sperm function, (2) the catalytic alpha subunit (C alpha), and in particular a germ cell specific isoform (C alpha 2), is essential for sperm motility but not for spermatogenesis or spermiogenesis, (3) that haploinsufficiency of the type I regulatory subunit alpha (RI alpha) of PKA causes sperm defects and infertility in both mice and humans.