Abstract Glioblastoma is the most frequent and aggressive primary brain tumor in adults. Currently, no curative treatment is available. Despite first-line treatment composed by the association of surgery, radiotherapy, and chemotherapy, relapse remains inevitable in a median delay of 6 to 10 months. Improving patient management and developing new therapeutic strategies are therefore a critical medical need in neuro-oncology. Gangliosides are sialic acid-containing glycosphingolipids, the most abundant in the nervous system, representing attractive therapeutic targets. The ganglioside GD3 is highly expressed in neuroectoderm-derived tumors such as melanoma and neuroblastoma, but also in gliomas. Moreover, interesting results, including our own, have reported the involvement of GD3 in the stemness of glioblastoma cells. In this review, we will first describe the characteristics of the ganglioside GD3 and its enzyme, the GD3 synthase (GD3S), including their biosynthesis and metabolism. Then, we will detail their expression and role in gliomas. Finally, we will summarize the current knowledge regarding the therapeutic development opportunities against GD3 and GD3S.