Weed is a small town located in Siskiyou County in the extreme northwest of California, not far from the Oregon border. George and Lennie first appear in the Salinas Valley. They have traveled hundreds of miles and may have been so unnerved by their near-death experience in Weed that they wanted to get as far away from the area as possible before lookinig for work.
The repeated references to the incident in Weed suggest that something of great importance to the story occurred there. Supposedly Lennie only wanted to feel a girl's dress, and she took it to have been something much more sinister. But when Lennie kills Curley's wife in the barn, George realizes that Lennie is changing. George, unlike the reader, does not understand exactly how Lennie came to kill Curley's wife, but it looks as though it involved sexual assault--which is exactly what it could have turned into if the girl hadn't put up a struggle and gotten her neck broken. And perhaps the girl in Weed might also have been sexually assaulted if she hadn't screamed and attracted a bunch of men.
When looking at the body of Curley's wife, half covered with hay, George says hopelessly, "I should have knew. I guess maybe way back in my head I did." What George should have known was that Lennie is changing. He is developing an ominous interest in the opposite sex, an interest he doesn't understand and cannot control.
It is a combination of two events, the one in Weed and the one at the ranch, that make George decide to kill his friend. George feels that Lennie has become a threat to society, and he feels personally guilty for the death of Curley's wife because he should have known that Lennie was potentially dangerous. The incident in Weed, which nearly cost George his own life, should have been a wake-up signal, but he let himself believe Lennie "meant no harm."