The objective of this experiment was to determine the effectiveness and crop safety of glyphosate vs. alternative herbicides for weed control in glyphosate-resistant alfalfa. Glyphosate-resistant alfalfa was established at two sites in Pennsylvania in 2004 and in 2005, and herbicides were applied either PRE or POST for weed control. Data were collected on herbicide performance, alfalfa and weed yield, and forage quality. Alfalfa forage response to weed control was variable and depended on weed severity. A single or split application of glyphosate provided similar or better weed control than conventionally based herbicide programs. The most differences from weed control occurred during the first harvest and dissipated in subsequent harvests. Cumulative alfalfa yield for the establishment year of the spring seeding was 26% lower in the untreated check relative to the mean of the herbicide-treated plots in 2004; but no differences were detected in 2005. Forage quality was highest where weed content of the forage was lowest. Effective management of weeds with herbicides during alfalfa establishment can improve forage yield and quality, and weed control is particularly important when summer annual weed populations are severe and emerge with the crop.