The Netherlands' hopes of reaching the World Cup finals suffered a major setback when the three-time runners-up slumped to a shock 2-0 defeat to Bulgaria.
The loss left the Dutch six points behind Group A leaders France, who beat Luxembourg 3-1, and down in fourth spot, three back from Sweden and two off Bulgaria with just the group winners guaranteed a place in the 2018 finals in Russia.
Elsewhere, Cristiano Ronaldo took his international tally to 70 goals as European champions Portugal beat Hungary 3-0 to stay in second spot behind Switzerland in Group B.
Belgium needed a goal two minutes from time by Romelu Lukaku to salvage a 1-1 draw against nine-man Greece as they stayed two points clear in Group H, although Roberto Martinez's team lost their 100 percent record in the process.
In Sofia, Bulgaria stunned the Dutch with two goals in the first 20 minutes, both coming from Spas Delev.
Delev pounced on a mistake by 17-year-old Matthijs De Ligt, Holland's youngest debutant since 1931, who misjudged a pass and allowed the striker to slot the ball past Jeroen Zoet.
Delev then made it 2-0 when he unleashed a stinging right-foot drive past Zoet.
The Dutch dominated large parts of the rest of the game but were thwarted by a solid Bulgarian defence while goalkeeper Nikolay Mihaylov pulled off a super save in the second period to deny Davy Klaassen.
Bas Dost had a weak header saved by Mihaylov as the Netherlands' evening petered out in a haze of possession and poor end product.
Group A table-toppers France, the 1998 champions and last year's Euro 2016 runners-up, saw Olivier Giroud open the scoring in Luxembourg just before the half-hour mark.
Luxembourg levelled after 34 minutes thanks to Aurelien Joachim's penalty, his country's first goal against France in 39 years.
But the minnows' joy was short-lived as Atletico Madrid striker Antoine Griezmann restored France's lead, also from the spot, just four minutes later.
Giroud scored his second of the evening after 77 minutes after being set up by Benjamin Mendy.
- Superb finish -
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In Lisbon, Portugal saw off Hungary, a team they shared six goals with at Euro 2016.
The win kept Portugal in second place in Group B, three points behind Switzerland, who earlier preserved their 100 percent record with a fifth win in five games, a 1-0 home victory against Latvia.
Porto striker Andre Silva opened the scoring after 30 minutes, converting a pass from Raphael Guerreiro for his fifth goal in six games for Portugal.
Six minutes later, skipper Ronaldo doubled the lead with a superb left-footed finish and the Real Madrid superstar made it 3-0 on 65 minutes with a clever free-kick for his 70th international goal.
Belgium stayed top of Group H but only after struggling to a 1-1 draw with Greece.
Missing the injured Eden Hazard, Belgium lacked a creative spark in Brussels and they were made to pay when Greece grabbed the lead just 20 seconds into the second period when Benfica striker Kostas Mitroglou latched on to a long ball to fire home his third goal of the qualifying campaign.
Greece were reduced to 10 men after 65 minutes when Panagiotis Tachtsidis was red carded for a crude lunge on defender Toby Alderweireld.
Everton striker Lukaku drove home from close range in the 89th minute to grab a share of the spoils before Georgios Tzavelas was sent-off in injury time.
Earlier on Saturday, Sweden crushed Belarus 4-0 to move to 10 points in Group A, three behind France, with Emil Forsberg scoring twice.
In Group H, Bosnia-Herzegovina also went on a goal spree with a 5-0 win over minnows Gibraltar, who have now conceded 22 goals in five games.
