Wimbledon: Monday 23 June to Sunday 6 July
Coverage: BBC TV, BBCi, Radio 5 Live and the BBC Sport website.
Roddick had never previously fallen before the third round at SW19
Two-time Wimbledon finalist Andy Roddick became the latest high-profile casualty when he was sent crashing by the unseeded Serb Janko Tipsarevic.
Roddick looked lost for ideas against a player who has never been past the fourth round of a Grand Slam, going down 7-6 (7-5) 5-7 4-6 6-7 (4-7).
Earlier, second seed Rafael Nadal came from a set down to beat the impressive Ernests Gulbis 5-7 6-2 7-6 (7-2) 6-3.
Tipsarevic now plays Dmitry Tursunov while Nadal faces Nicolas Kiefer.
Tursunov, seeded 25, proved too strong for British qualifier Chris Eaton and 27th seed Kiefer, a quarter-finalist in 1997, was in sensational form as he destroyed clay-specialist Martin Vassallo Arguello.
But ninth-seeded American James Blake saw his wretched Wimbledon record continue when he crashed 3-6 7-6 (10-8) 6-4 4-6 4-6 to the unseeded German Rainer Schuettler.
In six appearances at the All England Club, world number eight Blake has still never been past the third round.
Am I angry and disappointed in myself? Yes
Lindsay Davenport had already pulled out of the women's draw with a knee complaint and a terrible day for the United States was compounded when Roddick failed to reach the third round for the first time in eight Wimbledon appearances.
Roddick, the runner-up in 2004 and 2005, saw each of his eight break points go begging, while Tipsarevic converted both of his chances.
The 2003 US Open champion wasted three set points in the fourth set and was made to pay when Tipsarevic held his nerve in the tie-break, falling to his hands and knees in celebration on Centre Court.
"This means the world to me," said the world number 40, whose compatriot, third seed Novak Djokovic, was eliminated on Wednesday.
"I'm just glad that I won and Serbia will have more representatives in the men's singles draw".
I am very happy with this victory because I knew before the match that I was going to have a tough time against a very aggressive player
Roddick, on the other hand, was totally dejected with the manner of his defeat.
"Any chance I got I just choked it. So it's disappointing and not an easy thing to say. You want something so bad you almost squeeze too tight," he said.
"I didn't make the shots and there was nothing even positive in the misses.
"I was literally trying to make him play as I thought he was tight, but I should have made something happen and I didn't make it happen tonight. Zero, zero, zero.
"I probably won more total points up until the last one or two. I played horrific shots on break points. I put myself in a position to win that match in straight sets, I served huge but at the big moments I blinked.
"Am I angry and disappointed in myself? Yes."
Nadal, meanwhile, has now won his last 19 matches in all competitions and is bidding for a for a sixth title in seven tournaments.
Nadal is bidding to win his fourth consecutive tournament
"I am very happy with this victory because I knew before the match that I was going to have a tough time against a very aggressive player," Nadal told BBC Sport.
"He has a good serve, a strong forehand and backhand - he has a very good all-round game. "I improved throughout the match and I was playing well by the end."
The 22-year-old appeared taken aback as the Gulbis opened up with a display of unreturnable serves and blistering groundstrokes.
He struggled to establish his usual rhythm and his concentration looked particularly fragile after being denied a point at 4-4 on the Gulbis serve.
Nadal clearly reached a Gulbis drop-shot before Gulbis put his return wide, but the umpire adjudged Nadal's shot to have bounced twice.
French Open quarter-finalist Gulbis broke at 6-6 to take the first set but, evidently fired up, Nadal swiftly made inroads into the hitherto impeccable Gulbis serve, breaking at 1-1 and 3-1 before closing out the second set with a love service game.
Gulbis, the first ever Latvian to compete at a Grand Slam, saved a break point in the face of some electrifying tennis from Nadal, but the world number two's superiority shone through in the third-set tie-break.
Gulbis was visibly tiring and Nadal took his second of three break points at 4-3 up in the fourth set and completed the win on serve with a stunning, lopping passing shot down the line.
He is joined in the third round by Richard Gasquet, seeded eight and the beneficiary of fellow Frenchman Sebastien Grosjean's retirement at 6-2 6-2.
Mikhail Youzhny, the number 17 seed, eventually coming through 4-6 6-4 6-3 3-6 6-3 against Italy's Stefano Galvani.
Youzhny now meets 16th seed Radek Stepanek, a five-set winner against Viktor Troicki.
Another seed to fall was the number 24 Jarkko Nieminen, beaten 4-6 6-3 3-6 7-6 (8-6) 5-7 by Marin Cilic - the 19-year-old Croat reaching the second round at SW19 for the first time.
Tommy Haas goes on to play British number one Andy Murray after the former beat Tommy Robredo, seeded 23, and the latter Xavier Malisse - both winning is straight sets.