Glioblastoma multiforme (GBM), the most common primary malignant brain tumor in adults, is associated with high mortality. Current standard-of-care treatments, including surgery, radiation and chemotherapy, offer only palliation. Recent research in cancer therapy has shifted towards targeting the specific molecular aberrations that underlie the pathogenesis of cancers including GBM. Protein kinases are a family of enzymes that are key components in regulating cellular homeostasis. Protein kinases can be deregulated by several mechanisms, which contribute to cancer initiation and maintenance. Several protein kinases are important in gliomagenesis, thus representing new therapeutic targets in GBM. Low molecular weight inhibitors are the most commonly used agents to target protein kinases in the treatment of cancers. However, first-generation kinase inhibitors targeting only single kinases have demonstrated limited efficacy in unselected GBM patient populations. Several mechanisms of failure of monotherapy with single-targeted kinase inhibitors have been explained as new therapeutic strategies have emerged to overcome resistance. Simultaneous disruption of several kinases can be achieved by either multitargeted kinase inhibitors or combination of single-targeted kinase inhibitors with one another or with traditional cytotoxics. In this review, we will discuss the current clinical status of targeted therapy in GBM and recent approaches to target multiple kinases in this devastating cancer.