When a contestant gets the answer wrong on the first question.
Unless (starting with syndicated Season 9 of the US version) it's actually hard.
During a Celebrity Millionaire episode, Norm MacDonald asked Regis if using a 50:50 after he said what he was deciding between would leave those exact choices, like there's some guy in the back trying to sabotage him. Regis assured him that the two choices had been locked in for months note (this was back when the two choices eliminated by the 50:50 were not random but pre-selected by the writers, usually as the two choices the player was most likely to eliminate as incorrect)...but when Norm chose the 50:50 he was left with the two answers he was stuck between. Although the audience erupted into laughter, MacDonald gave Regis an absolutely majestic "WHADDID I TELL YA?" look. The whole ordeal can be seen here.
Of course, after the change to the 50:50 being "random", the computer left the answers the player was struggling between often enough that it led to the same allegations Norm brought up.
On another Celebrity episode, Jon Stewart was playing for an Alzheimer's Association of America, which led to this Crosses the Line Twice exchange during the $250,000 question:
Regis: The Alzheimer's Association would get a quarter of a million dollars if you get this. And if you don't, they'll be back down to $32,000.
Jon: Yeah, but they'd forget about it the next day.
October 2, 2002: Minda Lopez takes way too long on a question, leading to large chunks of her ruminations being edited out, followed by captions of "much later" and "much much later". On a question further up, Minda begins mulling over her options again, prompting Meredith to pull a Screw This, I'm Outta Here.
October 7-8, 2002: In the second month of her tenure, Meredith got smitten by a contestant and quickly proceeded to make things...awkward.
In one episode, a Phone-A-Friend responded "Meredith?" immediately after picking up the phone.
September 2012, Celebrity Week: Cheech Marin shows kindness and warmth to Meredith in his typical way, by presenting her with adult brownies.
October 2012: Brandon Saunders gets a question about a Fan Nickname for a cable network due to its late-night offerings. It quickly escalated, leading to him using Ask the Audience. The climax? 69% said "Skinemax". Freud Was Right, indeed.
Cedric the Entertainer
September 2, 2013: Unsurprisingly, Cedric delivered on his very first day, while discussing a question about hardware supplies with 18-year old contestant Nicholas.
Nicholas: I don't know what a caulk gun is. (audience laughs) Cedric: Trust me, by the time you get to college, you'll knowwhat it is! (audience laughs harder)
One contestant's Phone-A-Friend remained silent until saying "Hello?" at the 29th second.
A Fastest Finger question asked "Starting with Stop, put the traffic light sequence in order according to the British Highway Code", the answer being red, red and amber, green, amber (C-B-D-A). Nobody got it right. Even funnier is what host Chris Tarrant said to the audience before revealing the correct order — "If any of them gets this question wrong, don't let them drive you home."
Ralf Schnoor's Phone-A-Friend, overlapping with Moment of Awesome. With a million euros on the line, he calls his friend and starts the 30 seconds with (roughly) "Hi. How are you?" and proceeds to chat casually for another five seconds. The look on host Günther Jauch's face was priceless.