Brain lower-grade gliomas (LGG) usually occur in young adults who enjoy an active life. This tumor has a high risk of malignant transformation resulting in neurologic deterioration and finally death. Early and multistage therapeutic management can increase survival over 10 years. Preservation of functional neural networks and quality of life is crucial. In the era of evidence-based medicine, the issues discussed are those associated with the design, analysis, and clinical application of randomized controlled trials (RCTs) for LGG. RCTs should take account of the following: considerable variability in the natural course of LGG; limited prognostic value of molecular biology at the individual level; large variability of brain organization across patients; technical and conceptual progress of therapies over years; combination or repetition of iterative treatments, taken as a whole and not only in isolation; and long-term consequences on oncologic and functional outcomes. As it is difficult to translate the results of an RCT into benefits for a unique patient with LGG, personalized decisions must be made by considering the tumor behavior, individual pattern of neuroplasticity, and patient needs, and not by administrating a standardized protocol exclusively based on an RCT.