Field studies were conducted in five states at six locations from 2002 through 2003 to evaluate weed control and cotton response to early POST (EPOST), POST/POST-directed spray (PDS), and late POST-directed (LAYBY) systems using glyphosate-trimethylsulfonium salt (TM), s-metolachlor, trifloxysulfuron, prometryn, and MSMA. Early POST applications were made from mid May through mid June; POST/PDS applications were made from early June through mid July; and LAYBY applications were made from early July through mid August. Early season cotton injury and discoloration was minimal (< 1%) with all treatments; mid- and late-season injury was minimal (< 2%) except for trifloxysulfuron POST (11 and 9%, respectively). Annual grasses evaluated included barnyardgrass, broadleaf signalgrass, goosegrass, and large crabgrass. Broadleaf weeds evaluated included entireleaf morningglory, pitted morningglory, sicklepod, and smooth pigweed. For the EPOST, POST/PDS, and LAYBY applications, weeds were at cotyledon to 10 leaf, 1 to 25 leaf, and 2 to 25 leaf stage, respectively. Annual broadleaf and grass control was increased with the addition of s-metolachlor to glyphosate-TM EPOST systems (85 to 98% control) compared with glyphosate-TM EPOST alone (65 to 91% control), except for sicklepod control where equivalent control was observed. Annual grass control was greater with glyphosate-TM plus trifloxysulfuron PDS than with trifloxysulfuron POST or PDS, or trifloxysulfuron plus MSMA PDS (90 to 94% vs. 75 to 83% control). With few exceptions, broadleaf weed control was equivalent for trifloxysulfuron applied POST alone or PDS alone or in combination with glyphosate-TM PDS or MSMA PDS herbicide treatments (81 to 99% control). The addition of a LAYBY herbicide treatment increased broadleaf weed control by 11 to 36 percentage points compared with systems without a LAYBY. Cotton lint yield increased 420 kg/ha with the addition of s-metolachlor to glyphosate-TM EPOST treatments compared with systems without s-metolachlor EPOST. Cotton lint yield was increased 330 to 910 kg/ha with the addition of a POST herbicide treatment compared with systems without a POST/PDS treatment. The addition of a LAYBY herbicide treatment increased cotton lint yield by 440 kg/ha compared with systems without a LAYBY.