Romney notched a convincing victory in the heartland state of Illinois, quickly followed by a surprise endorsement from former Florida Governor Jeb Bush, the brother of former President George W Bush. There were also signs that major Republican campaign contributors are shifting more money in his direction.
Jeb Bush, an establishment figure within the party, has remained on the sidelines for much of the state-by-state primary contest.
His backing helped give Romney the aura of inevitability that has eluded him for months, despite a formidable financial and organisational advantage over his rivals.
"Now is the time for Republicans to unite behind Governor Romney and take our message of fiscal conservatism and job creation to all voters this fall," Bush said in a statement. He congratulated the other candidates "for a hard-fought, thoughtful debate and primary season".
Conservatives in the South and elsewhere distrust Romney's record as a Massachusetts governor, particularly his embrace of a requirement for state residents to buy health insurance. That initiative has drawn comparisons to Obama's health care reform, which Republicans staunchly oppose and hope to raise as a key issue in the November elections.
The primary race will go on, however. Romney's most dogged rival, Rick Santorum, is all but certain to claim more victories before the primary season ends. The conservative favourite looked ahead to this weekend's primary vote in the perhaps more welcoming Deep South state of Louisiana.
And an astonishing admission on Wednesday by one of Romney's top aides revived accusations that Romney is an inconsistent conservative.
Eric Fehrnstrom said primary-season policy positions may be no more lasting than squiggles on an Etch A Sketch, a mechanical drawing toy that children need only to shake for the image to vanish.
"I think you hit a reset button for the fall campaign. Everything changes," said Fehrnstrom during an interview on CNN.
"It's almost like an Etch A Sketch. You can kind of shake it up and restart all over again."
Still, Romney's triumph in Illinois on Tuesday night provided fresh evidence of electoral strength.
Santorum, a Catholic who is favoured by religious conservatives, now has almost no hope of overtaking Romney in the count of delegates who will choose the nominee at the Republican National Convention in August.
Romney picked up 41 delegates, to 10 for Santorum.
In The Associated Press count, Romney has 563 of the 1,144 delegates needed to clinch the nomination. Santorum has 263, former House Speaker Newt Gingrich 135 and Texas Representative Ron Paul 50. That gives the front-runner more than half, a pace that will let him seal his victory by the time the primaries end on June 26.
Another prominent Republican, former presidential candidate Bob Dole, gave Romney an additional boost on Wednesday by suggesting that Santorum is getting close to a decision point on whether to stay in the race or pull out. Dole, who became the Republican nominee in 1996 on his third try, said Gingrich is "probably finished, or almost finished".
"Rick, I think, he's got a real problem. In every race, Romney is going to pick up delegates," Dole told The Associated Press in a telephone interview on Wednesday. "It's getting close to the point where he's got to take a hard look at it."
Romney has benefited from the emergence of super PACs, independent committees that are allowed to raise money in unlimited amounts in support of candidates.
So far, he has benefited from more than $32 million in television ads from Restore Our Future, the entity that played the major role in wiping out Gingrich with attack ads in the days before the nominations contests in Iowa and Florida. More recently it has turned its attention to Santorum.
Additionally, campaign finance reports released on Tuesday showed that big donors to a Republican organisation founded by political strategist Karl Rove have boosted their financial support for the Romney-aligned super PAC in recent months.
"We're almost there," said Romney.
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