Development Hell: Conviction. It was originally slated for release in Christmas of 2007. They ended up scrapping it and starting over at least once. The new Conviction was revealed at E3 2009 and scheduled for February 2010, then April 10, and then finally released.
The Other Darrin: Pandora Tomorrow replaced both Grim and Lambert's voice actors. The change only lasted one game, and from Chaos Theory onwards, Grim and Lambert went back to their original voices.
In Blacklist, Sam is voiced by Eric Johnson, not Michael Ironside. Grim's voice actress also got changed again.
What Could Have Been: Conviction was earlier planned to use a "social stealth" system not unlike Assassin's Creed where Sam was a fugitive on the lam, evading the authorities by hiding himself using crowds, and have extensive environmental interactions (such as picking up many more things to use as a weapon) and would be animated to do actions more realistically from his location (as in, reaching over to an object from his current location to interact it instead of moving himself to a single pre-determined location and pose after hitting the button to interact like usual). This dramatically different direction was rather poorly received and the entire design was scrapped in favor of what Conviction was released as.