Earlier today, Matt Maiocco put together a rundown of his best and worst draft picks since 2000. His best pick was Patrick Willis and his worst pick was Kentwan Balmer. Both are very solid choices, but I would argue that Patrick Willis might not be the best choice for best draft pick since 2000.
I submitted some draft related content to Joel Thorman, the SB Nation NFL editor, and one of the questions was best draft pick of the last ten years. I went with Frank Gore. Although Willis is more likely to finish his career in the all-time NFL greats discussion, Frank Gore has accomplished so much in spite of a variety of hinderances. Gore came into the league having had major surgery on both of his knees. This caused him to drop to the third round. Following his rookie season, Gore had surgery on both of his shoulders.
In spite of numerous physical ailments, and amidst many questionable offenses, Frank Gore has somehow turned himself into one of the greatest running backs in franchise history. He is the franchise rushing leader (since the team entered the NFL) and has a great chance at finishing his career with the team. For a third round pick, I think that gives him a bump for this discussion.
I really can't find many problems with Maiocco's three choices and "honorable" mentions for worst draft pick since 2000. Kentwan Balmer and Rashaun Woods were no-doubt stinkers for the 49ers. It is of course an always interesting discussion with regards to Alex Smith. A year ago he likely would have been on this list, but a year later the discussion gets all the more interesting. You can make plenty of arguments for both sides, but he has certainly crept off the ledge to a certain degree.