Although Uruguay forward Edinson Cavani and Portugal's Cristiano Ronaldo will grab the headlines - the former for his two brilliantly goals and the latter for what could well be his World Cup farewell - Uruguay owed their 2-1 win to a superb all-round performance.
The Paris Saint-Germain striker had put Uruguay ahead early on by bundling Luis Suarez's cross home with his face after just seven minutes.
Uruguay and Portugal have faced off on two previous occasions, but never at the World Cup.
But their response to that was magnificent as they went quickly retook the lead, Rodrigo Bentancur teeing up Cavani for a magnificent first-time curling strike into the far corner on his right foot.
While Uruguay is advancing, it now must be concerned with the status of Cavani after he limped off the field and immediately called for a substitute.
Ronaldo's great start in Russian Federation allowed him to surpass the combined total of three goals he had scored in his previous three World Cups.
Bernardo Silva missed a golden opportunity to level the score in the 70th minute after Muslera bungled a save, leaving the ball loose in the box where it fell to the Man City man.
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"Uruguay scored with their first shot on our goal".
He did not even manage a touch of the ball in the Uruguay penalty area during a frustrating first half when his only effort was a free kick that was blocked by the wall.
22 - Luis Suarez gets a free kick outside the box and almost gets it to go but Portuguese goalkeeper Rui Patricio makes a nice save.
This is the first time Uruguay have won their opening four games to a World Cup tournament since 1930, with the fourth game in that run being their 4-2 victory over Argentina in the final. Furthermore, both players leave Russian Federation still in search of their first goals in the tournament's knockout stages.
Ronaldo nearly had a chance at goal on 20 minutes but a timely clearance by Gimenez six yards was enough to keep Ronaldo at bay.
Luis Suarez, left photo, and Cristiano Ronaldo will square off in the Uruguay-Portugal showdown in Sochi on Saturday. But with Uruguay sitting back, Portugal did equalise 10 minutes into the second half.
Uruguay coach Oscar Tabarez was complimentary of Ronaldo and the rest of the Portugal squad, noting several times Uruguay will be facing the reigning champions of Europe.