Treatment with hyperbaric oxygen can be a beneficial adjuvant therapy in various disorders characterized by compromised tissue oxygenation and perfusion. However, the effects of hyperbaric oxygenation cannot be simply explained as a compensation of the oxygen deficit. Hyperbaric oxigenation has a much broader influence and has the ability to alter protein expression, modulate signaling pathways and affect vascular structure and function. We discuss some of the most important uses of hyperbaric oxigenation for clinical conditions that involve abnormal vascular function. We present recent studies and insights into the mechanisms and effects of hyperbaric oxygen in the vasculature.