Glioblastoma multiforme (GBM) is the deadliest and the most heterogeneous brain cancer. The median survival time of GBM patients is approximately 8 to 15 months after initial diagnosis. GBM development is determined by numerous signaling pathways and is considered one of the most challenging and complicated-to-treat cancer types. Standard GBM therapy consist of surgery followed by radiotherapy or chemotherapy, and combined treatment. Current standard of care (SOC) does not offer a significant chance for GBM patients to combat cancer, and the selection of available drugs is limited. For almost 20 years, there has been only one drug, Temozolomide (TMZ), approved as a first-line GBM treatment. Due to the limited efficacy of TMZ and the high rate of resistant patients, the implementation of new chemotherapeutics is highly desired. However, due to the unique properties of GBM, many challenges still need to be overcome before reaching a 'breakthrough'. This review article describes the most recent compounds introduced into clinical trials as drug candidates for GBM chemotherapy.