1. Barry Sanders
Had he not retired when he did, after 10 seasons (all with the Lions of course), there's a fair chance we'd be talking about Sanders as the NFL's all-time leading rusher. As it is he's fourth with 15,269 yards, and Emmitt Smith needed to hang on as a shell of what he was for 15 total seasons to put up a little over 3,000 more yards (18,355) than Sanders did in his 10 seasons.
Two seasons along the lines of his final one (1,491 yards in 1998), plus a chunk of a third when he would have been 33 years old, and Sanders would have had more career yards than Smith. But, to paraphrase his unique retirement announcement, his desire to leave the game exceeded his desire to stay in it. And that had (and has) to be respected, even if it was massively disappointing for all NFL fans.
Sanders was a Pro Bowler in all 10 of his seasons, he led the league in rushing four times and he was a six-time first-team All-Pro. In 1997, his second-to-last season as it turned out to be, he rushed for 2,053 yards and won NFL MVP. He was not someone who looked like he was near the end that year, and physically he wasn't.
Sanders never rushed for less than 1,100 yards in his career, and he had less 1,500 yards from scrimmage just once. Only Jim Brown has averaged more rushing yards per game in a career. As a sidenote, Billy Sims is eighth on that career yards per game list.
Sanders was simply on a different level, leaving defenders looking like they were in slow motion. One of the all-time great running backs in NFL history will forever stand as the best running back in Lions' history.
Honorable Mentions: Altie Taylor (169-1975), Nick Pietrosante (1959-1965), Ace Gutowsky (1932-1938)