The ongoing political impasse in Northern Ireland is corroding and damaging the region, the Taoiseach has warned.
Leo Varadkar said the looming Brexit made the need to restore powersharing even more urgent.
Mr Varadkar told the Brookings Institution, an influential think tank in Washington DC: "It's our duty to work closely with the British Government and the Northern Ireland parties to find an agreed basis for the restoration of the institutions - and, given the wider circumstances - the task could not be more urgent."
The Taoiseach's speech came ahead of his participation in an event at Capitol Hill on Tuesday night to mark the 20th anniversary of the Good Friday peace accord, which largely ended Northern Ireland's violent conflict. The broker of the 1998 deal, Senator George Mitchell, was also an invited guest of honour at the commemoration.
"As with any peace, reaching agreement is far from the end of the journey - the path to reconciliation and stable politics can be a long and winding one and sometimes can be a bumpy ride," Mr Varadkar told an invited audience at the institution.
He said the ongoing deadlock between the DUP and Sinn Fein was undermining the 1998 Agreement.
"Just as important, it means that the direct voice of the people of Northern Ireland is not heard in the negotiations on the terms under which the United Kingdom will leave the European Union, even though these will be of great consequence to people in Northern Ireland and the border counties in particular," he added.
"The majority of people in Northern Ireland voted to stay in the European Union, even now the majority want to stay in the European Union's Single Market and Customs Union. For me I think that makes Brexit a real threat to the Good Friday Agreement."
On Brexit, Mr Varadkar told his audience that the only thing standing in the way of a "deep and comprehensive future relationship" between the UK and the EU was the former's "red lines".
He said: "While we deeply regret the decision of the United Kingdom to leave the EU, as we see it, there can be no upside. Nonetheless we must respect that decision."
"After decades of moving closer to its European partners, the UK has taken a decision to move farther away from us and that's why we must defend our national interests."
Mr Varadkar again stressed the need to maintain an invisible border on the island of Ireland post-Brexit.
"The economic benefits of this invisible border have been hugely significant - in terms of North/South trade and the all-island economy - and also and perhaps most importantly to the normalising of wider social and political relations across the island," he said.
"We are determined to ensure that these hard-won advances are not reversed.
"More widely, Brexit poses serious challenges for Ireland - and, given the strength of our ties to, and engagement with the UK, we will suffer more negative economic impacts than any other EU Member State.
"Our relationship with the UK is unique in terms of our shared history, geography and culture, and, while it represents an ever decreasing share, the UK remains our single most important economic partner.
"Ireland wants there to be a deep and comprehensive future relationship between the EU and the UK - one that maximises economic engagement and trade, one that ensures ongoing and continuing cooperation in areas such as combating terrorism and international crime, and also common foreign and security policies.
"The extent and possibility of this new deep and comprehensive relationship is limited only by the UK's own red lines."
Mr Varadkar was on the third day of his St Patrick's Day tour of the US. On Thursday he will hold bilateral talks with President Donald Trump at the White House.
Amid concerns the president's protectionist policies may spark a transatlantic trade war, Mr Varadkar said such an outcome would create no winners.
"Alongside our EU partners, we oppose any steps that raise barriers to trade, whether through the imposition of tariffs or otherwise," he said.
Mr Varadkar also told the century-old think-tank that Ireland was committed to efforts to eliminate poverty in sub-Saharan Africa.
"I believe that the major challenges that we face today, whether in Ireland, the United States, or across the world, will best be dealt with by acting together, and not in isolation," he added.
"Confident despite the doubts of today; certain that our united strength is the solution to global instability."