We conducted a series of field experiments to determine the role of several factors that might contribute to the inconsistent control of common lambsquarters with glyphosate. Experiments in 2006 and 2007 determined common lambsquarters response to glyphosate under a wide range of measured environmental conditions. Glyphosate was applied at 0.84 kg ae ha−1 plus 3.8 kg ha−1 ammonium sulfate (AMS) to 10-cm-tall plants on 18 dates in each year and to 20-cm-tall plants on 18 dates in 2007. Control was less for six application dates relative to control for 48 other dates. Poor control was attributed to rainfall on one of these six dates, but for the other five dates, regression analysis did not identify any significant relationships between environmental conditions (relative humidity, temperature at time of treatment, or minimum and maximum temperature pre- and posttreatment) and control, even though a wide range of conditions occurred. To determine the effects of plant growth stage on control, glyphosate was applied at 0.1 to 3.2 kg ha−1 plus 3.8 kg ha−1 AMS to 10- and 20-cm-tall plants at four sites. The glyphosate ED50 value (the effective dose that reduced shoot mass by 50% relative to nontreated plants) was 1.9 to 3.0 times greater for 20- than 10-cm-tall plants in three site-years, but was not affected by plant height in one site-year. We also conducted experiments to determine the effect of rainfall on glyphosate efficacy. Across years, common lambsquarters control increased from 44 to 75% as the interval between glyphosate application (0.84 kg ha−1 + 3.8 kg ha−1 AMS) and simulated rainfall increased from 0.5 to 4.0 h, respectively. Our results did not identify environmental conditions that explained reduced glyphosate efficacy in all cases, but they suggest that rainfall after application and plant height can be important factors contributing to the inconsistent control of common lambsquarters.