Jan Polanc moved over four minutes clear in the Giro d'Italia general classification after a sixth-place finish on stage 12 as Cesare Benedetti recorded his first professional win.
A couple of days dominated by the sprinters had seen little movement in the GC standings, with Polanc back in 23rd, five minutes and 24 seconds behind leader and UAE Team Emirates colleague Valerio Conti.
But that was all to change on Thursday as Polanc went with an early break and managed to stay the course.
The gap to the GC group was up to 15 minutes with 70 kilometres remaining, although he was dropped from the break just before the summit of a punishing climb 30km from the line.
Benedetti similarly fell away, but both riders recovered in the final stretch to secure memorable results.
Stage winner Benedetti, previously without a win on the UCI Tour at 31 years old, recovered time and again for an unlikely triumph.
The Italian benefitted from compatriot Gianluca Brambilla's gamble to go early, pipping Damiano Caruso and Eddie Dunbar at the finish.
Meanwhile, Polanc was sixth, 25 seconds back, and stormed to the top of the GC race, four minutes and seven seconds ahead of Primoz Roglic, with Conti back in third.
TEAM EMIRATES WELL SET
If Conti was to lose the lead, at least he had a team-mate able to pick up the slack.
Polanc said: "The team boss said I needed to go in the break. I was focused to get in the breakaway.
"At one point, I was thinking of the stage victory, for sure. But when we got the gap, everyone started saying to pull now.
"So, I think I did what I needed to do today.
"The stage tomorrow [Friday] will be big for the team. We didn't come here with GC ambitions, but we've had Valerio in pink for quite a few days and now, for me, it's also really nice."
1. Cesare Benedetti (BORA - hansgrohe) 3:41:49
2. Damiano Caruso (Bahrain-Merida)
3. Eddie Dunbar (Team INEOS)
4. Gianluca Brambilla (Trek-Segafredo) + 0:02
5. Eros Capecchi (Deceuninck-Quick Step) + 0:06
1. Jan Polanc (UAE Team Emirates) 48:49:40
2. Primoz Roglic (Jumbo-Visma) + 4:07
3. Valerio Conti (UAE Team Emirates) + 4:15
1. Arnaud Demare (Groupama-FDJ) 194
2. Pascal Ackermann (BORA - hansgrohe) 183
3. Richard Carapaz (Movistar Team) 50
King of the Mountains
1. Gianluca Brambilla (Trek-Segafredo) 40
2. Giulio Ciccone (Trek-Segafredo) 32
3. Primoz Roglic (Jumbo-Visma) 22
Polanc might have the lead now, but there is scope for further GC changes on Friday. There are three notable climbs on the 188km ride from Pinerolo to Ceresole Reale.