The field of genetic prenatal diagnosis has seen remarkable advances in terms of prevention of birth defects and genetic diseases in the last 40 years. This progress is due to the operators’ experience with new genome studies and molecular biology analysis. In the meantime, the most sophisticated ultrasonography equipment has made it possible to perform fetal procedures in early pregnancy as well as in the preimplantation period, thus making prenatal diagnosis increasingly accepted by couples wishing to plan their offspring and reducing the anxiety of waiting for the diagnostic response, and, in severe cases when chosen by the woman, the possibility of terminating the pregnancy in the first trimester. In the new era of genetic screening using combined tests and noninvasive prenatal testing (NIPT), we have had a decrease in invasive prenatal diagnostic procedures and a progressive increase in chorionic villus sampling (CVS) compared to amniocentesis for chromosomal indications. In this paper, we describe the invasive sampling techniques performed at Microcitemico Hospital–Cagliari in the last 40 years by fetal blood sampling (FBS), amniocentesis, CVS, and preimplantation genetic diagnosis (PGD) applied to prevent the most common fetal genetic disorders.