Now Roger Federer and company are on the ropes.
Isner jolted Federer with his big serve and booming groundstrokes Friday, winning 4-6, 6-3, 7-6 (4), 6-2 to give the U.S. a 2-0 lead against Switzerland in the first round of the Davis Cup.
Isner challenged the 16-time Grand Slam champion in long rallies on the indoor clay court, sending Federer to his first loss in Davis Cup singles in eight years and silencing a Swiss crowd unaccustomed to such outcomes.
"I thought he played great," Federer said. "He played it tough and served great when he had to. I just missed a couple more opportunities than he did and that's what cost me the match."
The 26-year-old Isner called it the "biggest win of my career thus far."
"I'm very proud of it," he said. "I played those break points down very well. It turned the match a little for me."
The upset was preceded by a riveting opening singles match, with Fish outlasting Stanislas Wawrinka 6-2, 4-6, 4-6, 6-1, 9-7.
"Mardy put forth a great effort," Isner said. "That was so gutsy. It took a lot of pressure off of me."
"It's been a difficult day for us," Federer said, adding: "We still have a chance to go through. I'm going to enjoy the challenge."
Before a crowd of 7,000 at Fribourg Forum, Federer started in routine fashion by winning the first set without dropping serve. Isner broke in the sixth game of the second set, but failed to exert any pressure in the third.
Still, the third-ranked Federer couldn't take capitalize on break-point chances in the sixth and eighth games -- winning just one of his 12 opportunities in the match -- and the set drifted into a tiebreaker.
Isner never trailed and clinched on his first set point with a subtle volley at the net that left Federer no chance.
The fourth set turned on the fifth game when Isner rallied from 0-40 down with three big serves and two blistering forehand winners.
Federer never recovered. Isner reeled off four straight games, ending the match by rifling a backhand winner crosscourt.
"I thought John finished it well," Federer said. "It's always a little bit easier to swing from the hip when you are a break up and two sets to one."
U.S. captain Jim Courier had higher praise for the 17th-ranked Isner.
"I don't know I have ever seen anyone finish a match against Roger Federer the way he did today. That was pretty amazing," Courier said.
Isner had lost his two previous encounters with Federer, both on hard courts.
If 17th-ranked Isner needed any inspiration for his match with Federer, he found it in Fish's earlier 4-hour, 26-minute victory -- the third-longest Davis Cup singles match involving a U.S. player since 1989 when tiebreakers were introduced in the competition.
Fish managed to rally after wasting a match point at 5-4 in the deciding set and won six games later with a cross-court volley winner at the net.
"It's certainly up there, there's no doubt about it," said Fish, when asked how it ranked among his best wins. "It's a good win to beat Stan, period. Clay is his best surface, his favorite surface and it's in his home country. I'll take that away, for sure."
A 95-minute final set included wild shifts in momentum and emotion before the eighth-ranked American improved his record to 3-0 against the 28th-ranked Wawrinka.
"He did everything to win," Wawrinka said. "He played more aggressively in the fifth set."
Fish was up a break at 4-3 and held serve only after going 0-40 down, saving the first chance with an excellent lob. Serving for the match, Fish saved a break point before a long rally on match point ended with Fish wrongfooted by Wawrinka's forehand winner.
Wawrinka made it 5-5 when Fish sent a forehand long, but dropped serve to give Fish a 8-7 lead on his third break opportunity.
In a fluctuating final game, Fish trailed 15-40, won three straight points, then wasted a second match point when Wawrinka unleashed a backhand service return down the line. Fish's 14th ace created a third, and decisive, match point to give Courier's team a perfect start.
"I'm obviously proud of the guys," Courier said. "But we have a long way home to win that third match out of five."