The transient receptor potential vanilloid 4 (TRPV4) is a nonspecific cation channel which serves as a hub protein capable of integrating multiple external physical and chemical stimuli such as changes in temperature, cell volume, pressure, flow, or arachidonic acid metabolites. These stimuli could be considered stress signals, raising the possibility that activation of TRPV4 may be a component of stress-induced homeostatic pathways. Systemic activation of TRPV4 leads to life-threatening increases in permeability culminating in pulmonary edema and cardiovascular collapse. Conversely, genetic knockout or pharmacological antagonism have not been correlated with major systemic changes. In choroid plexus epithelial cell lines, pharmacological stimulation of TRPV4 initiates a complex combination of transepithelial ion movements involving both anions and cations that is accompanied by a substantial and sustained increase in permeability. Remarkably, under low agonist concentrations, these permeability changes are immediately reversible by the addition of a TRPV4 antagonist, suggesting a change in transcellular flux rather than a direct effect on junctional permeability. With the background of known localization of specific transporters in choroid plexus epithelial cells, it is possible to construct minimal-sufficient models that couple energy gradients to the net secretory direction of solute and water flow. These models are useful for designing experiments to elucidate the complex but functionally important pathways regulating electrolyte movements and accompanying changes in the blood–cerebrospinal fluid barrier.