Novak Djokovic became the most high-profile casualty so far at this year's French Open as he was beaten 6-4 6-4 6-4 by Germany's Philipp Kohlschreiber.
The fourth seed looked out of sorts and was broken twice in the first and second sets of the third-round match.
Kohlschreiber, who had only won two of his previous six matches at Roland Garros, broke at 4-4 in the third set and served out for a famous victory.
World number two Roger Federer beat Paul-Henri Mathieu 4-6 6-1 6-4 6-4.
Frenchman Mathieu looked capable of causing a huge upset when he deservedly took the first set and had the Court Phillipe Chatrier crowd in raptures.
But Federer, bidding for a record-equalling 14th Grand Slam title, stepped up his game and from then on the result never looked in doubt.
The Swiss faces Tommy Haas - through to the fourth round for only the second time in nine attempts after seeing off Jeremy Chardy 7-5 6-3 4-6 6-4 - with a quarter-finals berth at stake.
Asked about the demise of possible semi-final opponent Djokovic, Federer said: "Winning the semi-final is not winning the tournament, so it doesn't change anything."
Djokovic had been touted as one of the main threats to top seed and defending champion Rafael Nadal after pushing him all the way in Madrid two weeks ago.
But against Kohlschreiber, who was contesting a third-round match for the first time after a five-set win over 2003 champion Juan Carlos Ferrero, Djokovic met his match.
"I was disappointed with the way I was performing," said the Serb. "I couldn't find the rhythm throughout the whole match.
"I was trying to find the comfort zone but my legs were really stuck.
"I was trying not to be frustrated with my unforced errors and trying to stay positive and wait for my chances, but he didn't give me any.
"He played tactically really smart and I had no solutions. But, as I said before, the opening rounds are very dangerous because the players are lower ranked and they have nothing to lose."
The Serb claimed the first break of serve, in game four, but from 4-1 up the wheels came off for the 2008 Australian Open champion.
Roddick fell at the first hurdle on his previous two appearances in Paris
Kohlschreiber reeled off five games in a row to wrap up the opening set and it was much the same story in the second.
Djokovic won the first game but then allowed his 25-year-old opponent to dominate proceedings by taking another five games in a row.
The world number four never looked like turning his two-set deficit around.
Kohlschreiber, seeded 29, broke in game nine of the third set with a stunning backhand passing shot down the line and easily served out for the biggest win of his career.
The German, who goes on to play Tommy Robredo, had last hit the headlines at the Australian Open in 2008 when he stunned Andy Roddick in the third round.
Roddick continued his impressive progress on Saturday with a 6-1 6-4 6-3 victory over Marc Gicquel of France.
The former world number one took two out of two break points and saved three on his serve before winning the first set.
Roddick's big serving and much-improved shot selection and movement saw him to victory with a single break in both the second and third sets.
He is only the second American to reach the fourth round since Andre Agassi in 2003, the same year Roddick won his only major title at the US Open.
"It's three matches, which is a lot better than I've done before," said Roddick, who made only 11 unforced errors and now plays Gael Monfils - a 6-2 4-6 6-3 6-1 victor over Jurgen Melzer.
Roddick has reached at least the semi-finals at the other three Grand Slam tournaments but his best French Open performance before this year was reaching the third round on his debut in 2001.
"I like my chances maybe more than the other years," said the 26-year-old. "I feel like I'm moving a little bit better on this stuff. I'm able to kind of slide into my forehand."
Fifth seed Juan Martin del Potro continued his fine run of form to overcome Igor Andreev 6-4 7-5 6-4.
The ever-improving Argentine will meet Jo-Wilfried Tsonga for a place in the last eight after the Frenchman stormed to a 6-2 6-2 6-2 win against Christophe Rochus.
Del Potro, 20, is the second-youngest player left in the men's draw and is one of only four players to have beaten top seed Rafael Nadal in 2009.