Infertility is a difficult and stressful condition that impacts about 15 percent of couples attempting to conceive for the first time [1]. In about half of these cases a male factor is causative and, in general, constitutes a major health issue. While the cornerstone of the evaluation of male infertility remains the basic semen analysis, the sperm penetration assay (SPA) is a useful laboratory test for predicting the capacity of an individual male’s spermatozoa to fertilize a female oocyte. This assay supplements standard semen parameters and aids clinicians in identifying couples who will have a high chance of success with in vitro fertilization. The test was first developed in the 1970s and gained momentum when, in 1976, Yanagimachi and colleagues noted that enzymatic removal of the zona pellucida of hamster ova allowed penetration by human spermatozoa [2]. The goal of the SPA is to measure the spermatozoa’s ability to undergo capacitation, acrosome reaction, fusion and penetration through the oolemma (egg plasma membrane), and decondensation within the cytoplasm of hamster oocytes resulting in the formation of the male pronucleus [3].