Field experiments were conducted in Platte County, Missouri, during 2006 and 2007 to evaluate PRE, POST, and PRE followed by (fb) POST herbicide programs for the control of glyphosate-resistant waterhemp in soybean. All PRE fb POST treatments resulted in at least 66 and 70% control of glyphosate-resistant waterhemp in 2006 and 2007, respectively. Control of glyphosate-resistant waterhemp was less than 23% with lactofen and acifluorfen in 2006, but at least 64% in 2007. Variability in control likely resulted from differences in trial locations and a population of protoporphyrinogen oxidase (PPO)–resistant waterhemp at the Platte County site in 2006 compared with 2007. In both years, glyphosate resulted in less than 23% control of glyphosate-resistant waterhemp and provided the least control of all herbicide programs. Programs containing PRE herbicides resulted in waterhemp densities of less than 5 plants/m2, whereas the POST glyphosate treatment resulted in 38 to 70 plants/m2. Waterhemp seed production was reduced at least 78% in all PRE fb POST programs, from 55 to 71% in POST programs containing lactofen and acifluorfen and by only 21% in the POST glyphosate treatment. Soybean yields corresponded to the level of waterhemp control achieved in both years, with the lowest yields resulting from programs that provided poorest waterhemp control. PRE applications of S-metolachlor plus metribuzin provided one of the highest net incomes in both years and resulted in $271 to $340/ha greater net income than the glyphosate-only treatment. Collectively, the results from these experiments illustrate the effectiveness of PRE herbicides for the control of glyphosate-resistant waterhemp in glyphosate-resistant soybean and the inconsistency of PPO-inhibiting herbicides or PPO-inhibiting herbicide combinations for the control of waterhemp populations with multiple resistance to glyphosate and PPO-inhibiting herbicides.