Volcanic-hosted massive sulfide (VHMS) deposits, the ancient analogues of “black smoker” deposits that currently form on the seafloor, are the products of complex mineral systems involving the interaction of seawater with the underlying volcanic pile and associated magmatic intrusions. Light stable isotopes, particularly those of oxygen, hydrogen and sulfur, have had a strong influence in determining sources of ore fluids and sulfur as well as elucidating geological processes important in the VHMS mineral systems. Oxygen and hydrogen isotope data indicate that evolved seawater was the dominant ore-forming fluid in VHMS mineral systems through geological time, although a small proportion of deposits, including high sulfidation and tin-rich deposits, may have a significant, or dominant, magmatic-hydrothermal fluid component. Higher-temperature (> 200 °C) interaction of evolved seawater alters the rock pile below the seafloor, producing δ18O depletion anomalies at the deposit and district scales that can be used as a vector to ore. In contrast, lower-temperature hydrothermal alteration results in δ18O-enriched zones that commonly cap mineralized positions. An apparent decrease in the degree of high temperature 18O depletion with time may relate to the increasing importance of felsic-dominated host successions in younger deposits. δ18O anomalies have potential as an exploration tool, and have contributed directly to discovery. The other important contribution of stable isotopes to understanding the VHMS mineral system is quantification of the contribution of sulfur sources. Conventional δ34S data, when combined with Δ33S data acquired using recently developed technologies, indicate that the dominant sulfur source is igneous sulfur, either leached from the volcanic pile or introduced as a magmatic volatile (these sources are not distinguishable). The thermochemical reduction of seawater sulfate is also an important, but subordinate, sulfur source. Estimation of the proportion of seawater sulfate with geological age indicate that, on average, it has increased from 5–10% in the Archean to 20–25% in the Phanerozoic. This most likely reflects the increase in seawater sulfate contents through geological time. Although untested as an exploration tool, variations in sulfur isotope data may have utility is discriminating fertile from barren sulfide accumulations or providing vectors to ores at the deposits scale. As exploration tools, light stable isotopes suffer from a relatively high cost and slow turn-around time. If these limitations can be overcome, and new analytical methods can be developed, light stable isotopes may emerge as another tool for exploration, particularly as discoveries are made at greater depth and under cover.