The endothelium is a highly dynamic structure lining the inside of blood vessels that exhibits physical and chemical properties that are critical determinants of overall vascular function. Physically, the endothelium constitutes a semipermeable barrier. Chemically, the endothelium synthesizes numerous factors such as reactive oxygen species (ROS) that can act as autocrine and paracrine signaling molecules. Oxidative stress results when ROS levels increase to levels that cause cellular injury, and, in the endothelium oxidative stress leads to barrier disruption. Endothelial barrier disruption also results from increased cytosolic calcium through store-operated calcium (SOC) entry channels. Although it is known that ROS can interact with and regulate some ion channels, relatively little is known about the interaction of these species with components of endothelial SOC entry channels, the canonical transient receptor potential (TRPC) proteins. Here we review our current understanding of ROS-mediated TRPC channel function and how it affects SOC entry and endothelial barrier disruption.