Although glyphosate is typically used as a nonselective herbicide, low rates have the potential to provide selective control of seedling annuals in the understory of established perennial plants. In a repeated experiment on two adjacent sites at a single location near Alturas, CA (2009 and 2010), we evaluated the efficacy of glyphosate at several different rates on medusahead and nontarget species in northern California sagebrush scrub. We applied glyphosate at 10 rates ranging from 0 to 709 g ae ha−1 (0 to 18 oz product acre−1) at three separate timings in each trial: mid-March (medusahead in early seedling stage), late April to early May (tillering), and late May to early June (boot to early head). Plots measured 3 m by 9 m (10 ft by 30 ft) and were arranged in randomized complete blocks with four replications for each rate and timing. We visually estimated vegetative cover for all dominant species in July before medusahead seed drop using three 1-m2 quadrats per plot. Medusahead cover declined with increasing rates of glyphosate, and the middle application timing (at tillering) was the most effective. In rate series regression models, we achieved 95% control of medusahead with 160 g ae ha−1 glyphosate in midseason 2009, compared with 463 g ae ha−1 in early season and 203 g ae ha−1 in late season. In 2010, we achieved 95% control with 348 g ae ha−1 in midseason, compared with > 709 g ae ha−1 in early season. Medusahead seed production reflected changes in cover, though individual plants tended to produce more seed at low densities. We attribute reduced control early in the season and poorer overall control in 2010 to greater tolerance of medusahead to glyphosate at lower temperatures. Treatment effects on big sagebrush, as indicated by shoot tip vigor, were minor, although the midseason timing caused a slight reduction in vigor. These results show that low rates of glyphosate (158 to 315 g ae ha−1) at a treatment timing corresponding to medusahead tillering can give economical and effective control of medusahead without long-term damage to big sagebrush.