Drug delivery to the central nervous system (CNS) remains a challenge in neuro-oncology. Despite decades of research in this field, no consensus has emerged as to the best approach to tackle this physiological limitation. Moreover, the relevance of doing so is still sometimes questioned in the community. In this paper, we present our experience with CNS delivery strategies that have been developed in the laboratory and have made their way to the clinic in a continuum of translational research. Using the intra-arterial (IA) route as an avenue to deliver chemotherapeutics in the treatment of brain tumors, complemented by an osmotic breach of the blood-brain barrier (BBB) in specific situations, we have developed over the years a comprehensive research effort on this specialized topic. Looking at pre-clinical work supporting the rationale for this approach, and presenting results discussing the safety of the strategy, as well as results obtained in the treatment of malignant gliomas and primary CNS lymphomas, this paper intends to comprehensively summarize our work in this field.