Significance: Voltage-gated proton channels are increasingly implicated in cellular proton homeostasis. Proton currents were originally identified in snail neurons less than 40 years ago, and subsequently shown to play an important auxiliary role in the functioning of reactive oxygen species (ROS)-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. Molecular identification of voltage-gated proton channels was achieved less than 10 years ago. Interestingly, so far, only one gene coding for voltage-gated proton channels has been identified, namely hydrogen voltage-gated channel 1 (HVCN1), which codes for the H_V1 proton channel protein. Over the last years, the first picture of putative physiological functions of H_V1 has been emerging. Recent Advances: The best-studied role remains charge and pH compensation during the respiratory burst of the phagocyte NADPH oxidase (NOX). Strong evidence for a role of H_V1 is also emerging in sperm biology, but the relationship with the sperm NOX5 remains unclear. Probably in many instances, H_V1 functions independently of NOX: for example in snail neurons, basophils, osteoclasts, and cancer cells. Critical Issues: Generally, ion channels are good drug targets; however, this feature has so far not been exploited for H_V1, and hitherto no inhibitors compatible with clinical use exist. However, there are emerging indications for H_V1 inhibitors, ranging from diseases with a strong activation of the phagocyte NOX (e.g., stroke) to infertility, osteoporosis, and cancer. Future Directions: Clinically useful H_V1-active drugs should be developed and might become interesting drugs of the future. Antioxid. Redox Signal. 23, 490–513.