"Baseball America" ranked Cain as the 13th-best prospect in baseball in 2005, as well as the Giants' top prospect. Cain attended spring training in 2005, but he began the season with the Fresno Grizzlies of the Triple-A Pacific Coast League (PCL). In 26 starts, Cain had a 10–5 record and innings pitched. He finished fifth (tied with R.A. Dickey and Adam Wainwright) in the PCL in wins and fourth with a 4.39 ERA (behind Kevin Jarvis's 3.38, Chris Oxspring's 4.03, and Édgar González's 4.37). He led the league with 176 strikeouts.