The cortex develops hand-in-glove with its cerebrospinal fluid (CSF)-filled ventricles whose walls harbor neural stem cells (NSCs) destined to become  neurons and glia. Within each ventricle, the choroid plexus (ChP), comprising the blood-CSF immune barrier, secretes a half-liter of CSF/day, delivering growth factors to proliferating NSCs and flushing wastes into the glia-lymphatic “brain-drain”. Despite its importance for brain morphogenesis and function, the biology of the ChP/CSF-ventricular system, and its interplay with NSCs at the CSF-brain interface, remains enigmatic. My lab’s objective is to probe the molecular logic of the ChP/CSF-ventricular system by studying its dysregulation in hydrocephalus and related CSF disorders – the most common reasons for brain surgery in children. To do this, my lab has developed multi-omic, computational, and physiological methods, including in vivo measurements of CSF dynamics. Using these methods, we (i) identified a druggable kinase-regulated switch of ChP immuno-secretory function that holds potential for the treatment of multiple forms of acquired hydrocephalus (Nat Med, 2017; Cell, 2023) and (ii) discovered >10 congenital hydrocephalus (CH) disease genes, establishing a clinically-impactful “NSC paradigm” of disease (Neuron, 2018; Nat Med, 2021; Nat Neurosci, 2022; Neuron 2022). However, (i) our understanding of the mechanisms of the ChP’s secretory and immune-barrier functions remain rudimentary; (ii) the genetic causes of most CH cases and other CSF disorders remain unsolved; and (iii) the mechanisms by which patient mutations disrupt CSF dynamics and parenchymal function via the NSC dysregulation are poorly characterized. We are positioned to address these gaps by leveraging orthogonal data sets generated from our world’s largest cohorts of CSF disorders and patient-derived/humanized model systems. Results will elucidate fundamental aspects of human brain development; re-classify CSF disorders with a molecular nomenclature that increases precision for prognostication and treatments; and catalyze the development of targeted therapies.