The Conservatives have beaten Labour in the Hartlepool by-election, with a Tory MP elected for the first time in the current constituency's history.
Tory candidate Jill Mortimer - who defeated Labour rival Paul Williams by nearly 7,000 votes - hailed the result as a "truly historic" moment.
It comes as a blow to Sir Keir Starmer's efforts to win back support in traditional Labour heartlands.
The Tories are also making gains from Labour in English council elections.
On a walkabout in Hartlepool with the victorious Tory candidate, Boris Johnson said her win was a "mandate for us to continue to deliver" for the north-east of England and the rest of the country.
"If there is a lesson out of this whole election campaign across the whole of the UK is that the public want us to get on with focusing on their needs and their priorities, coming through the pandemic and making sure we build back better," added the prime minister.
Sir Keir said he was "bitterly disappointed" by the results.
The Labour leader said the party had "lost the trust of working people, particularly in places like Hartlepool," but added: "I will take full responsibility for fixing things."
He said Labour had "not made a strong enough case to the country" and he promised to set out changes in the next few days to help the party "reconnect" with lost voters.
The Hartlepool constituency was formed in 1974 and had returned a Labour MP in every vote since - until Thursday's poll.
Ms Mortimer hailed it as a "truly historic" result, adding: "Not only that, I am the first woman ever to be elected as MP for this town.
"Labour have taken people in Hartlepool for granted for too long.
"I heard this time and time again on the doorstep and people have had enough and now, through this result, the people have spoken and have made it clear it is time for change."
Diane Abbott, an ally of Sir Keir Starmer's predecessor Jeremy Corbyn, tweeted: "Crushing defeat for Labour in Hartlepool. Not possible to blame Jeremy Corbyn for this result. Labour won the seat twice under his leadership. Keir Starmer must think again about his strategy."
Another Corbyn ally, union boss Len McCluskey, warned Labour faced a "continuous downward decline" unless Sir Keir started "talking about the radical alternative for ordinary working people".
"People don't know what his vision is. People don't know what Labour stand for anymore," said the Unite general secretary.
He told Nick Robinson's Political Thinking podcast he did not trust Sir Keir and had not spoken to him since Mr Corbyn's expulsion from the Parliamentary party last year.
Mr Corbyn, who now sits as an independent MP, tweeted: "With millions not voting, these results show a loss of hope.
"We must offer a bolder vision to transform people's lives and give them the confidence to strive for a more equal world."
But key figures from the centrist wing of the party say the Hartlepool defeat, which saw a 16% swing from Labour to the Conservatives, showed Labour had not changed enough.
Lord Adonis, who served under Tony Blair and Gordon Brown, said the party was in "no man's land" under Sir Keir, who he described as a "transitional leader".
He warned "it could be curtains for Labour" unless it became a "modernising, centrist, dynamic" party.
And former Hartlepool MP Lord Mandelson said it was clear from his conversations with voters in the town that Mr Corbyn was "still casting a very dark cloud over Labour" and that the party had more work to do put that era behind it.
He told BBC Radio 4's Today programme the Hartlepool defeat was down to "two Cs: Covid and Corbyn".
Labour's loss of Hartlepool in a by-election is the most dramatic illustration yet that the party has so far failed to connect with the Leave-supporting, working class voters they lost heavily in 2017 and 2019.
Support for the Brexit Party, which registered 26% in Hartlepool in 2019, collapsed - the successor Reform party secured just 1% of the vote.
It looks as though the Conservatives picked up the Brexit Party's former support, in line with the proportion of Leave voters preferring the Conservatives to Labour to the order of 3/4 to 1.
However, the swing to the Conservatives of 16% is more than can be accounted for by the collapse of the Brexit Party.
Labour's vote fell 9 points to 29%, so the party clearly lost some of its 2019 support, as well as suffering from the movement of Brexit Party voters to the Conservatives.
Part of the explanation may lie in the success of independent candidate, Sam Lee, who won 10% of the vote.
Together with the pattern in key wards there is clearly a debate about whether Labour can win support from Leave voters by ignoring Brexit as it has in the past 12 months.
The Conservative gain of Northumberland council is a further illustration of the success of the Conservatives in Leave voting areas.
Conservative Ms Mortimer won with 15,529 votes, while Labour's Mr Williams received 8,589.
The Hartlepool seat came back into contention after its former Labour MP, Mike Hill, resigned in March.
The by-election was one of a raft of elections taking place across Britain on Thursday, with voters picking representatives for the Scottish Parliament and Welsh Senedd, as well as mayors and local councils in England, and police and crime commissioners.
The result is more evidence of the long term shift in politics where areas that had chosen Labour for decades were less and less convinced.
That didn't start with Boris Johnson and didn't even start with Brexit.
The success of the vaccine programme has no doubt helped the Tories.
But Keir Starmer has questions to answer as well.