Since the establishment of in vitro fertilization, it became evident that almost half of the couples failed toachieve fertilization and this phenomenon was attributed to a male gamete dysfunction. The adoptionof assisted fertilization techniques particularly ICSI has been able to alleviate male factor infertility bygranting the consistent ability of a viable spermatozoon to activate an oocyte. Single sperm injection, bypinpointing the beginning of fertilization, has been an invaluable tool in clarifying the different aspects ofearly fertilization and syngamy. However, even with ICSI some couples fail to fertilize due to ooplasmicdysmaturity in relation to the achieved nuclear maturation marked by the extrusion of the first polarbody. More uncommon are cases where the spermatozoa partially or completely lack the specific oocyteactivating factor. In this work, we review the most relevant aspects of fertilization and its failure throughassisted reproductive technologies. Attempts at diagnosing and treating clinical fertilization failure aredescribed.