Humidity cell tests (HCTs) are long-term (20 to >300 weeks) leach tests that are considered by some to be the among the most reliable geochemical characterization methods for estimating the leachate quality of mined materials. A number of modifications have been added to the original HCT method, but the interpretation of test results varies widely. We suggest that the HCTs represent an underutilized source of geochemical data, with a year-long test generating approximately 2500 individual chemical data points. The HCT concentration peaks and valleys can be thought of as a “chromatogram” of reactions that may occur in the field, whereby peaks in concentrations are associated with different geochemical processes, including sulfate salt dissolution, sulfide oxidation, and dissolution of rock-forming minerals, some of which can neutralize acid. Some of these reactions occur simultaneously, some do not, and geochemical modeling can be used to help distinguish the dominant processes. Our detailed examination, including speciation and inverse modeling, of HCTs from three projects with different geology and mineralization shows that rapid sulfide oxidation dominates over a limited period of time that starts between 40 and 200 weeks of testing. The applicability of laboratory tests results to predicting field leachate concentrations, loads, or rates of reaction has not been adequately demonstrated, although early flush releases and rapid sulfide oxidation rates in HCTs should have some relevance to field conditions. Knowledge of possible maximum solute concentrations is needed to design effective treatment and mitigation approaches. Early flush and maximum sulfide oxidation results from HCTs should be retained and used in environmental models. Factors that complicate the use of HCTs include: sample representation, time for microbial oxidizers to grow, sample storage before testing, geochemical reactions that add or remove constituents, and the HCT results chosen for use in modeling the environmental performance at mine sites. Improved guidance is needed for more consistent interpretation and use of HCT results that rely on identifying: the geochemical processes; the mineralogy, including secondary mineralogy; the available surface area for reactions; and the influence of hydrologic processes on leachate concentrations in runoff, streams, and groundwater.