Fusarium head blight (FHB), caused by the fungus Fusarium graminearum, is associated with grain contamination with mycotoxins such as deoxynivalenol (DON) and zearalenone (ZEA), a potent estrogenic secondary metabolite. Unlike DON, ZEA is rarely the focus to FHB-related research, and as such, less is known about factors affecting its production during FHB epidemics. The objective of this study was to quantify the contamination of wheat grain with ZEA as influenced by temperature (20, 25, and 30^oC), relative humidity (RH, 70, 80, 90, and 100%), FHB index (IND), grain maturation, simulated last-season rainfall (0, 5, and 10 days of pre-harvest rainfall), and harvest timing. ZEA concentrations were low during early stages of grain development (25-31 days after anthesis [DAA]) but rapidly increased at latter stages (35 to 51 DAA) in field experiments, particularly under rainy conditions. Five or ten consecutive days with simulated rainfall shortly before harvest greatly increased ZEA contamination. Similarly, extremely high levels of ZEA were observed in grain from spikes exposed to 100% RH across all tested temperatures and mean IND levels under controlled conditions. Interestingly, at RH ≤ 90%, ZEA concentrations were very low at all tested temperatures, even at IND above 90%. Temperature affected ZEA contamination at 100% RH, with significantly higher mean levels of the toxin at 20 and 25^oC than at 30^oC. Grain harvested early and not exposed to simulated rainfall had lower mean ZEA than grain harvested late and subjected to pre-harvest rainfall. This study was the first to associate ZEA contamination of grain from FHB-affected wheat spikes with temperature and moisture and show through designed experiments that early harvest could be a useful strategy for reducing ZEA contamination. These results constitute new, valuable information for understanding this complex disease-toxin system and developing guidelines for managing FHB and minimizing grain yield and quality losses. In particular, finding from studies of conditions driving the production of ZEA will be helpful for predicting when this mycotoxin will likely be a concern and warrants more attention in terms of monitoring and testing.