Primary Infertility and Failed Fertilization “Doctors, look, we finally have a baby!” A couple with primary infertility who had been infertile for 16 years, holding up the fluttering urine test sheet, with the brightest smiles, loudly conveyed their long-awaited news to us, and even to the whole world! In an instant, we automatically stopped what we were doing, containing crystal tears, and expressed our most sincere congratulations with hugs! Six months ago today, this couple, who had been running around for many years seeking medical treatment, came to our center with a tired pace and the mindset of “treating a dead horse as a living horse”. I received them warmly. After the routine examination, it was found that the female partner had normal ovulation with normal ovulation, except for the age-related poor ovarian reserve capacity; the male partner’s semen analysis showed normal sperm density, viability and vitality; and the examination results did not support the possibility of immune infertility. According to the above examination results, I immediately thought: there might be a problem of sperm-egg union during fertilization. As a first step, we chose the husband’s semen artificial insemination technique, which means that the husband’s semen is injected directly into the uterine cavity after being optimized in vitro. The failure of all three IUIs further supported my initial suspicions. In the second step, we opted for IVF assisted conception treatment. After ultra-ovulation, 6 eggs were eventually obtained and, considering the possible barriers to fertilization, we used 3 eggs for conventional in vitro fertilization-embryo transfer (i.e., free union of sperm and egg in an in vitro setting) and the other 3 eggs for intracytoplasmic single sperm microinjection (i.e., using a micro-penetrating needle, sperm are injected directly into the egg to fertilization). As I expected, none of the three eggs from the conventional in vitro fertilization-embryo transfer were fertilized, whereas the three eggs from the intracytoplasmic single sperm microinjection were well fertilized and all developed into good embryos. Thus, 16 days after we transferred the embryos into the mother’s uterus, we were able to share with the couple the good news they had been waiting for for 16 years. What are the factors associated with impaired sperm-egg union during fertilization? During normal fertilization, the sperm and egg recognize each other and the sperm first binds to the zona pellucida, undergoes the acrosome reaction, and then penetrates the zona pellucida and fuses with the egg membrane. Therefore, a disorder at either stage of the fertilization process can cause fertilization failure. Defective sperm function, abnormalities of the zona pellucida or oocyte membrane are the main causes of fertilization disorders. In contrast, the use of intracytoplasmic single sperm microinjection technique can largely correct the occurrence of sperm-egg free association disorders. Therefore, we must consider the occurrence of sperm-egg binding disorder in couples with unexplained infertility for many years and use intracytoplasmic single sperm microinjection technique to help conception when the indications are met. While we are happy for this couple, we wish all the infertile couples in the world a good journey in their long search for medical treatment. Although diseases can destroy our healthy bodies, our healthy minds and bodies, and even our happy families, as long as we insist on the concept of winning, on the good hope, and on the vision of future happiness, we can definitely overcome this stumbling block and reach the other side of sharing the joy of family life.