Human gliomas are the most common primary central nervous system neoplasm, and they are a complex, heterogeneous, and difficult disease to treat. In the past two decades, advances in molecular biology have revolutionized our understanding of the mechanism by which these neoplasms are initiated and progress. While surgery, radiation therapy, and chemotherapy have roles to play in the treatment of patients with gliomas; these therapies are self-limited because of the intrinsic resistance of glioma cells to therapy, and the diffusely infiltrating nature of the lesions. It is now known that malignant gliomas arise from a number of well-characterized genetic alterations and activations of oncogenes and inactivation of tumor suppressor genes. These genetic alterations disrupt critical cell cycle, growth factor activation, apoptotic, cell motility, and invasion pathways that lead to phenotypic changes and neoplastic transformation. Research in each of these fields has uncovered potential therapeutic targets that look promising for disease control. Gliomas can now be modeled with fidelity and reproducibility using several transgenic and knockout strategies. Transgenic mouse models are facilitating the testing of various therapeutic strategies in vivo. Finally, the recognition of the putative brain tumor stem cell, the tumor initiating cell in brain cancer, provides an enticing target through which we could eliminate the source of the brain tumor with increased efficacy and less toxicity to normal tissues. In this review, we provide an up-to-date discussion of the many of key technologies and tools that are being used in molecular biology to advance our understanding of the biological behavior of human malignant gliomas.