Scottish champions Celtic and last season's quarter-finalists Porto both lost at home to crash out of the Champions League in the third round of qualifying.
There was a close escape for last season's semi-finalists Ajax while Istanbul Basaksehir exited at the hands of Olympiacos.
Celtic manager Neil Lennon admitted they "shot themselves in the foot" after losing 4-3 at home to CFR Cluj to go down 5-4 on aggregate.
The Hoops made a storming start to the second half to go 2-1 ahead through goals from James Forrest and Odsonne Edouard but Scott Brown's handball allowed Billel Omrani to net from the spot.
Ryan Christie soon put Celtic back in front but Omrani quickly levelled again on the rebound in the 80th minute to put the Romanians ahead on away goals.
George Tucudean then netted with the last kick of the game to seal the visitors' victory.
"We had the lead twice and we have given it away," Lennon said.
Porto went out on away goals to Krasnodar after conceding three goals in the first half in a 3-2 defeat.
After scoring twice in reply to get the aggregate back to 3-3, the Portuguese threw players forward but dogged defending kept the Russians ahead.
Ajax avoided becoming the third former European champions to be eliminated as they survived a nervous evening to beat PAOK 3-2 to take the tie 5-4 on aggregate.
The Dutch hosts faced elimination when their former youth player Diego Biseswar scored for PAOK in the 23rd minute to put the Greeks 3-2 ahead on aggregate.
Ajax captain Dusan Tadic had one penalty saved, but scored a second to draw level.
A Nicolas Tagliafico header finally put Ajax ahead in the 79th, before PAOK's rough, physical style handed Ajax a third penalty converted by Tadic.
Biseswar scored again in stoppage time for PAOK to again put Ajax in danger, but the Dutch champions held on to win.
"It was a tough evening. I'm glad we got there in the end, but don't ask me how," Ajax midfielder Donny van de Beek said.
"It's a very tough team to play against."
APOEL of Cyprus won 2-0 at Azerbaijan's Qarabag to go through to the playoffs 3-2 on aggregate while Red Star and FC Copenhagen took 11 penalties apiece before Jonas Wind's miss sent the Serbian team through.
Wind and Red Star's Radovan Pankov took two penalties apiece in the shootout because Red Star had finished the game with 10 men.
Other teams to reach the Champions League playoffs were Club Brugge, Dinamo Zagreb, LASK and Rosenborg.
CHAMPIONS LEAGUE PLAYOFFS DRAW:
CFR Cluj (ROU) v Slavia Prague (CZE) APOEL (CYP) v Ajax (NED) LASK (AUT) v Club Brugge (BEL) Dinamo Zagreb (CRO) v Rosenborg (NOR) Young Boys (SUI) v Red Star (SRB) Olympiacos (GRE) v Krasnodar (RUS)