Prime Minister Malcolm Turnbull is preparing for a cabinet reshuffle as soon as this weekend.
It comes after Nationals leader Warren Truss and Trade Minister Andrew Robb announced their exit from politics.
The move has also triggered the Nationals' first election for a party leader in 26 years, with Barnaby Joyce expected to assume the role.
After securing the Trans-Pacific Partnership - and free trade deals with China, Japan and Korea - Trade Minister Andrew Robb says he is ready to leave politics for the next challenge.
"I'm no spring chicken but, at the same time, I'm 64 and in excellent health. I'm young enough to do other things and there are other things that I want to, especially in business, and also if I can to try and assist the cause of mental health, the acceptance and the progress in the mental health space."
And in a day of departures, Nationals leader - and deputy prime minister - Warren Truss confirmed his retirement from federal parliament.
Speaking in parliament, he said he would leave at a time convenient to the government, likely within the next few days.
Mr Truss says serving in politics - at a federal and local level - for the past 40 years has been a great privilege.
"I came from a small farming district and went to a very small state school, and I had the privilege now to become Deputy Prime Minister of our country...I want to thank the people of Australia for the opportunity that they have given me to serve in this regard. I'll take away many happy memories and I hope that people may be kind enough to recognise that I have made something of a contribution towards public life in this country."
Tributes for the two politicians went on for over an hour, with Prime Minister Turnbull keen to emphasise the contributions made by the pair.
"Andrew Robb, Mr Speaker, has without question in his two-and-a-half years as Trade Minister, been the most successful Trade Minister in our history. He has put in place some of the most important building blocks for our future...Warren's leadership of the National Party has been a source of great wisdom for the leaders of the Liberal Party, great stability, great generosity. He is absolutely committed, has always been committed, to the strength of the Coalition."
Mr Truss' departure creates a vacancy for the leadership of the Nationals.
Agriculture Minister Barnaby Joyce is expected become the party's new leader - and deputy Prime Minister - unopposed.
Not afraid to speak his mind, Mr Joyce has made a number of headlines with his outspoken views since he entered Parliament in 2005.
Educated by Jesuits in Sydney, the self-described social conservative used his maiden speech in Parliament to label abortion the "slavery debate of our time".
His opposition to the Howard coalition government's plan to privatise Telstra also put him in the headlines.
He went on to cross the floor 19 times under the Howard coalition government.
In 2015, he made international headlines with his threat to euthanase Hollywood actor Johnny Depp's dogs after it was found they had illegally entered the country.
Warren Truss says he has every confidence that Barnaby Joyce will make a very capable leader.
"He has obviously got a high profile in the community. He has a different style to me, but you would expect that from a new leader. And while his leadership will be different, I am sure it will be constructive - that he will be a good working relationship with Malcolm Turnbull and our Coalition partners."
Nationals MP Darren Chester told Sky News says he believes Mr Joyce has the qualities to do well as the party's leader.
"Well Barnaby Joyce and I are great mates. I have had a lot of good times with Barnaby in parliament - and in terms of social things. We have played a bit of touch footy together and that sort of stuff. I think he is a really robust regional character and a good strong political figure, who has shown throughout his political career that he has got the courage to stand up for regional Australia."
Speaking on the ABC, Nationals MP Michael McCormack, who withdrew from the Nationals' leadership contest, conceded Barnaby Joyce does divide opinion with what he described as a frank and forthright manner.
But he says that does not mean he won't be a capable party leader.
"Look, he does but he is also revered by great sections of the rural community. And certainly it would be an interesting ride."
Opposition leader Bill Shorten says Barnaby Joyce's views are so different from Prime Minister Malcolm Turnbull's that it could be a point of tension, instead of unity.
"They have a diametrically different view of the world. If the leader has a different view on many policies to the deputy leader [deputy prime minister], that's not good for the unity of the government. Clearly, Barnaby Joyce was a fan of Tony Abbott's and not Malcolm Turnbull's so I think it is cementing division into the future in this government."
The exit of Andrew Robb and Warren Truss has added to the case for a major ministerial reshuffle in the Turnbull government, expected as early as this weekend.
Two ministerial seats remain vacant after scandals forced the resignations of Minister for Cities Jamie Briggs and Special Minister of State Mal Brough.
The future of Human Services Minister Stuart Robert is also uncertain after an internal review was launched into whether he breached ministerial standards by helping a friend - and Liberal Party donor - sign a mining deal in China in 2014.
