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In September 1965, the NFWA launched a strike against California's grape growers alongside the Agricultural Workers Organizing Committee (AWOC), a Filipino-American labor group. The strike lasted five years and expanded into a nationwide boycott of California grapes. The boycott drew widespread support, thanks to the highly visible campaign headed by Chavez, who led a 340-mile march from Delano to Sacramento in 1966 and undertook a well-publicized 25-day hunger strike in 1968."I am convinced that the truest act of courage, the strongest act of manliness, is to sacrifice ourselves for others in a totally non-violent struggle for justice," Chavez declared, in a speech read on his behalf when his first hunger strike ended. "To be a man is to suffer for others. God help us be men."

The grape strike and boycott ended in 1970, with the farm workers reaching a collective bargaining agreement with major grape growers that increased the workers' pay and gave them the right to unionize. The NWFA and AWOC had merged in 1966 to form the United Farm Workers Organizing Committee, which in 1971 became the United Farm Workers of America (UFW).