Clinical trials are prospective scientific studies involving human participants and form the basis for identifying new treatments for diseases like brain tumors. A clinical trial should be designed to provide definitive results for a study question. Therefore, investigators should understand the principles underlying the design, execution and analysis of clinical trials. In addition to the application of basic principles germane to the design of all clinical trials, studies in neuro-oncology also involve unique challenges in case definition, selection of endpoints and definition of response. This review begins with enumeration of the basic principles of clinical trial design including reduction of bias and variability, and concludes with a review of study design factors of particular relevance for neuro-oncology.