2010. Jim DeMint killed absolutely any likelihood of the GOP capturing the Senate that year.
Not single handedly. Even if you give credit to Jim DeMint for costing us CO, DE and NV, you are still one seat short, and Republicans got their strongest possible candidate in WA the next closest seat. Granted, if Capito had run in 2010 she might have won, but unlike in 2014, the GOP was not ready to capitalize on the environment there from an organizational standpoint. Though Raese was obviously not a good choice, I don't think there were any better ones aside from Capito that would have made a difference.
On the other hand, the establishment blew CT and CA by rallying to the moneybag computer lady and moneybag wrestling lady respectively instead of the moderate former Republican Congressmen Tom Campbell and Rob Simmons. Ironically the one person who spreads the blame wholly to both sides (tea party and establishment) is Ann Coulter.
At the end of the day Republicans had a bad map (the 2004 map) to go into 2010 with and even if they had run the table they still would have come up short most likely by a seat or two.