This research was aimed at understanding how far and how fast glyphosate-resistant (GR) Palmer amaranth will spread in cotton and the consequences associated with allowing a single plant to escape control. Specifically, research was conducted to determine the collective impact of seed dispersal agents on the in-field expansion of GR Palmer amaranth, and any resulting yield reductions in an enhanced GR cotton system where glyphosate was solely used for weed control. Introduction of 20,000 GR Palmer amaranth seed into a 1-m2 circle in February 2008 was used to represent survival through maturity of a single GR female Palmer amaranth escape from the 2007 growing season. The experiment was conducted in four different cotton fields (0.53 to 0.77 ha in size) with no history of Palmer amaranth infestation. In the subsequent year, Palmer amaranth was located as far as 114 m downslope, creating a separate patch. It is believed that rainwater dispersed the seeds from the original area of introduction. In less than 2 yr after introduction, GR Palmer amaranth expanded to the boundaries of all fields, infesting over 20% of the total field area. Spatial regression estimates indicated that no yield penalty was associated with Palmer amaranth density the first year after introduction, which is not surprising since only 0.56% of the field area was infested with GR Palmer amaranth in 2008. Lint yield reductions as high as 17 kg ha−1 were observed 2 yr after the introduction (in 2009). Three years after the introduction (2010), Palmer amaranth infested 95 to 100% of the area in all fields, resulting in complete crop loss since it was impossible to harvest the crop. These results indicate that resistance management options such as a “zero-tolerance threshold” should be used in managing or mitigating the spread of GR Palmer amaranth. This research demonstrates the need for proactive resistance management.