Malignant gliomas are the most frequent and most malignant intracranial neoplasms. In spite of extensive clinical trials and irrespective of aggressive surgery, radiotherapy and chemotherapy, the outcome is very poor and limited progress has been made in the last three decades. Several innovative targeted molecular therapies that are tailored to deregulate the signalling pathways involved in malignant progression have opened new and challenging treatment opportunities and offer hope for an improved outcome in the future. Furthermore, in the field of conventional cytotoxic agents, new drugs or combinations are continuously investigated, widening the therapeutic armamentarium. This paper reviews this rapidly evolving field, focuses on the results of the use of these agents in clinical trials and discusses the main methodological challenges that need to be dealt with before relevant progress in the outcome of malignant gliomas can be yielded.