Issa's and Royce's departures come amid other gathering head winds for the GOP, including national polls showing a growing voter preference for Democratic congressional candidates; robust fundraising and grass-roots support for candidates challenging Republican incumbents; and the drag of President Trump's unpopularity on his party.
"It kind of reminds me of 2006," said Rep. Patrick J. Tiberi (R-Ohio), referring to the year Democrats picked up 31 seats and retook the majority after 12 years. "It felt like you were running uphill every day in terms of the environment, and I think that's how it feels now."
Tiberi is among the departing Republicans, resigning his House seat on Thursday to begin a job leading the Ohio Business Roundtable. He cited family reasons as the driving factor for his decision, but he said the political reality was hard to ignore.
At least 29 House seats held by Republicans will be open in November; only 22 GOP seats were open in 2006, and 19 Democratic seats in 2010. The 1994 "Republican revolution" that swept the GOP into power after decades of Democratic rule saw 27 Democratic retirements.
A striking feature of the slate of GOP retirements is the number of committee chairmen, including Royce and Issa, who had already lost or were about to lose their leadership posts as a result of party-governed term limits. The prospect of losing control of the chamber may have made staying in office even less palatable — but it also will leave the House GOP conference with far fewer experienced lawmakers.
"They saw 2006 or 2010, and they're like: 'You know what? I'm going to take a different road,' " Tiberi said.
House Republican rules limit chairmen to three consecutive terms. Five sitting chairmen who have exhausted their tenures, including Royce, are forgoing reelection. Top GOP leaders cite those party rules as a primary reason for the spate of retirements.
"Very few people are excited about going from a committee chairmanship to being a rank-and-file member, and those who do it, like Darrell Issa, don't do it for very long," said Rep. Steve Stivers (R-Ohio), who leads the National Republican Congressional Committee. "It's just the circle of life, and we have to be ready for it. We have good candidates, and I feel good about our chances in these seats."
Indeed, not all the retirements present clear pickup opportunities for Democrats. Many of the open seats are in districts considered solidly Republican, vacated by lawmakers who might have easily secured reelection.
The obstacles for the GOP, however, are unmistakable. Democrats need a net gain of 24 seats to capture the majority.
Democrats average a 13-point lead over Republicans in surveys over the past month pitting a generic Democratic candidate against a Republican. That's larger than the six- to eight-point lead that analysts say Democrats need to retake the House. So far this cycle, the NRCC has been outraised by its Democratic counterpart, the Democratic Congressional Campaign Committee, though the NRCC maintains a cash-on-hand advantage and a major independent committee supporting House GOP candidates this week reported raising $26 million in 2017 to help protect the GOP majority.
Republicans also face the possibility that districts could be redrawn in Democrats' favor over the coming months. A federal judge invalidated North Carolina's GOP-drawn map this week, and cases are pending over lines Republican legislatures drew in Pennsylvania and Wisconsin.
Republicans are at less risk of losing the Senate, where only a few GOP incumbents are vulnerable and many Democrats are seeking reelection in states Trump won in 2016. But the decision of Sens. Bob Corker (R-Tenn.) and Jeff Flake (R-Ariz.) to retire and the surprise victory of Sen. Doug Jones (D-Ala.) in a special election last month offered Democrats a plausible, if improbable, path to the majority.
Issa built a national profile as the chief congressional antagonist to Barack Obama and his administration during Issa's tenure as ranking Republican and then chairman of the House Oversight and Government Reform Committee, between 2008 and 2015. He later targeted former secretary of state Hillary Clinton, as she prepared to seek the presidency, over her response to the deadly 2012 attacks on Americans in Benghazi, Libya.
But Issa's hold on his San Diego-area district became increasingly tenuous in recent years, and he barely fended off a Democratic challenger in 2016.
In a statement Wednesday, Issa did not give a reason for his departure but reflected on a two-decade political career that included jump-starting the process that led to the 2003 recall of California Gov. Gray Davis (D). He declined to elaborate in a brief interview Wednesday.
"Eighteen years is a long time, and I'm looking forward to another chapter in my life," he said. "We'll see what it is."
Several other House Republicans said in interviews Wednesday that they had been struck by the intensity of the grass-roots "resistance" to Trump and Republican officeholders. "I've had opposition for 38 years; it's now matriculated into hatred," said Rep. Christopher H. Smith (R-N.J.).
But some insisted that Republicans could withstand the onslaught and keep their majority in November. Stivers said the comparison to the prior waves is unfair, pointing to the GOP's 5-0 record in special House elections for seats held by Republicans in the past year.
"It would be nice if [Democrats would] win something before you try to make it into 2006," he said.
Democrats, however, outpaced their past performances in each of those districts. And they will have at least three more chances this year to claim GOP seats before Election Day. Special elections are scheduled this year to fill vacant seats in Pennsylvania, Arizona and Ohio.
Jesse Ferguson, a former senior DCCC aide who worked at the committee during the 2010 cycle, said all signs point to 2018 resembling that year's wave — but in reverse.
"There's no question some Democrats in 2010 ran for the hills. But this time, it looks like Republicans are trying to find the lifeboat on the Titanic," he said. "Retirements are a harbinger of what the party is facing, and you have some Republicans jumping ship because they are worried about their reelection and others leaving because they don't want to come back to a party that is in the minority."
Rep. John Yarmuth (D-Ky.), who was first elected to the House in the 2006 wave, said he's already detected a "sense of inevitability" among his GOP colleagues — and a touch of political gallows humor.
Yarmuth is the top Democrat on the House Budget Committee and stands to claim the gavel if Republicans lose their majority. "People say, 'Enjoy your chairmanship,' " he said about comments he's gotten from Republicans.
Scott Clement contributed to this report.