Abstract Increasing manufacture and use of engineered nanoparticles is leading to a greater probability for release of engineered nanoparticles into the environment and exposure to organisms. In particular, zinc oxide (ZnO) is toxic, although it is unclear whether this toxicity is due to the zinc oxide nanoparticles, dissolution to Zn2+, or some combination thereof. The goal of this study was to determine the relative solubilities of both commercially available and in-house synthesized ZnO in matrices used for environmental fate and transport or biological toxicity studies. Dissolution of ZnO was observed in nanopure water (7.18–7.40 mg/L dissolved Zn, as measured by filtration) and Roswell Park Memorial Institute medium (RPMI-1640) (∼5 mg/L), but much more dissolution was observed in Dulbecco's modified Eagle's medium, in which the dissolved Zn concentration exceeded 34 mg/L. Moderately hard water exhibited low Zn solubility, likely because of precipitation of a Zn carbonate solid phase. Precipitation of a Zn-containing solid phase in RPMI also appeared to limit Zn solubility. Equilibrium conditions with respect to ZnO solubility were not apparent in these matrices, even after more than 1,000 h of dissolution. These results suggest that solution chemistry exerts a strong influence on ZnO dissolution and can result in limits on Zn solubility from precipitation of less soluble solid phases. Environ. Toxicol. Chem. 2012;31:93–99. © 2011 SETAC