From an evolutionary point of view, the gametes are the cells in the body that matter the most as they are the ones who transmit their genes to the next generation ensuring continuation of the species. Being able to generate mature oocytes in vitro is of great interest. Oocytes are the key to totipotency and are able to reprogram somatic cells in approximately one day. In addition, in contrast to a clump of pluripotent stem cells, once the developmental program has started, fertilized oocytes develop into a clump of cells with positional information and the possibility to differentiate into both the embryonic and the extraembryonic lineages that form a complete developing and viable organism. How to instruct pluripotent stem cells to become oocytes in vitro is still unclear and even though the first steps to obtain mouse oocytes have recently been successfully demonstrated, inducing meiosis progression and folliculogenesis in vitro are still far from being understood and have not yet been accomplished. In humans, the specific molecular niche that leads to correct oogenesis is less understood. Here, we discuss the current status of in vitro differentiation of human pluripotent stem cells into gametes, in particular to oocytes.