Due to the Cowboys switch to the 4-3 from the 3-4, under new defensive coordinator Monte Kiffin, DeMarcus moved to defensive end, along with Anthony Spencer, who started his NFL career opposite Ware at left side linebacker, but was a defensive end at college. Under Kiffin's system, Ware was able to dedicate himself as a pass-rusher. Despite becoming a pure pass rusher, on his first play as a defensive end, Ware picked off Giants quarterback Eli Manning. In Week 3 against the St. Louis Rams, he became the Cowboys' all-time sack leader, surpassing Harvey Martin's 30-year-old record of 114.