On the 91st episode during the 11th season, a question with the "Ask the Audience" lifeline being used ends up showed 100% of the audience providing the correct answer, which was the very first time it has ever happened in the syndicated version of the show.

The "Phone a Friend" lifeline was removed because too many people were googling the answers on the other line of the phone which is usually a form of cheating.

During the Halloween week in Season 11, the show had a Halloween theme. The icons for the lifelines were changed and they had different names that represent a Halloween theme, which were picked out by the show's Facebook fans. The "Ask the Audience" was renamed to "Pick the Audiences' Brains" and the "Jump the Questions" were each renamed to "Bat the Question Away". In addition, a new lifeline called "Crystal Ball" was provided during that week. It would reveal the amount of money behind the question, helping the player decide whether they really want to jump the question. This lifeline was also used occasionally during Season 11.

After Season 11, Meredith Vieira resigned from the show so she can move on to do other things with her career. As of Season 12, Cedric the Entertainer took Meredith's place as the host.

After one whole season, Cedric the Entertainer left the show after Season 12 ended due to his busy schedule in his career. As of Season 13, actor Terry Crews took Cedric's place as host.

For the 14th season, the show gets a new host, and brings back some of the early features of the game. The 50/50 lifeline returns, replacing the option to jump a question; most notably, the randomly selected dollar amounts for the first ten questions are replaced by the original "ladder" format in which contestants begin with lower-value questions and gradually move to questions worth increasingly greater amounts.

After one season, Terry Crews left the show so he can focus on hosting the show World's Funniest Fails on Fox. At the beginning of Season 14, the Bachelor's host Chris Harrison has taken Terry's place as host.

As of 2019 there have been 12 million dollar winners Kevin Olmstead's $2,180,000 was the biggest win in the show's history and Nancy Christy was the first female winner.

John Carpenter the first million dollar winner was the first contestant to use a lifeline in the final question as he called his father.

At the beginning of season 9, some of the rules of the game have changed. The "clock format" was replaced with a "shuffle format." The amount of questions on the money tree went from 15 questions to 14 questions and they were split into two rounds. The first round consists of 10 questions with categories and the second round would contain the last 4 questions without the categories and is also referred to as "Classic Millionaire." The dollar amounts in the first round would be hidden and randomly mixed up and then the categories would be added in and mixed up randomly. Then after the player answers a question correctly, the amount of money behind the question will be revealed and added into a bank, accumulates the player's winnings throughout the game. If the player chooses to walk during the first round, they will receive half of the amount in their bank and if they choose to walk anytime during the round two, they will receive all the winnings in their bank. However, if the player gets the answer to a question wrong during the first round, they will lose the entire bank and leave with a $1,000 consolation prize. If they get the answer to a question in the second round wrong, they will end up walking with $25,000.

At the beginning of season 9, the entire studio had a makeover. The hot seat was retired and replaced with a podium in the center where the host and the contestant would stand during the show. A big LCD screen hanging in the studio displays the question and the answers. In season 10, the podium was replaced with a clear tall table and the staircases had colored lights added.

At the beginning of season 9, the lifelines were changed. The "Double Dip" and "Ask the Expert" lifelines were replaced with two "Jump the Question" lifelines, which allow the player to skip the question without having to answer it. However, the player forfeits the amount of money hidden behind the question. The "Jump the Question" cannot be used on the very last question, which is the million dollar question. The "Ask the Audience" lifeline still remains the same.

At the beginning of Season 13, one of the "jump the question" lifelines was removed and replaced with a new lifeline called the +1, which allows the player to call down their friend or whoever came with them to the show to come and assist them with the question.

From 2001-2006 there was a Who Wants to be a Millionaire Play It attraction at Disney's MGM Studios in Orlando, Florida where the attraction was a replica of the Millionaire set however there were a few differences such as contestants playing for points instead of money also the show was hosted by a cast member however on rare occasions the real Millionaire would be taped live from the Play It attraction and would be hosted by Regis