Former Victorian premier Denis Napthine and senior MP Terry Mulder have formally ended their careers in politics, triggering two state by-elections.

Key points: Former Victorian premier Denis Napthine has resigned

Former Victorian premier Denis Napthine has resigned Dr Napthine served in Parliament for 27 years

Dr Napthine served in Parliament for 27 years Former transport minister Terry Mulder also resigned

Former transport minister Terry Mulder also resigned The resignations have triggered two state by-elections

Dr Napthine announced his resignation saying he was bowing out of parliamentary life with many happy memories and lifelong friends.

"It has been an absolute honour and privilege to serve in the Victorian Parliament for 27 years as Member for Portland and South West Coast," he said in his resignation speech.

Dr Napthine, Victoria's 47th premier, served as Liberal leader twice during his career.

He was elected to Parliament to represent the seat of Portland on the west coast in 1988 until the seat was abolished in 2002.

Since then he has represented South West Coast, a region Dr Napthine served with passion.

"To live, work and represent this magnificent part of Victoria has been a great joy and I have loved representing this region each and every day," he said.

In 1999 he replaced Jeff Kennett following the Liberal election defeat and held the position until he was challenged and defeated by the current Mayor of Melbourne, Robert Doyle, in 2002.

He assumed the leadership again in March 2013, following the sudden resignation of then leader Ted Baillieu.

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After the party lost the November 29, 2014 election, Dr Napthine announced he would step down.

Dr Napthine grew up on a farm at Winchelsea and studied veterinary sciences and business administration.

He and his wife Peggy were involved in community services involving the intellectually disabled and have three adult sons.

In his resignation speech, Dr Napthine said signing the state up to the National Disability Insurance Scheme (NDIS), with its headquarters in Geelong, was one of his proudest achievements.

"The NDIS provides new and better opportunities for people with disabilities, their families and carers," he said.

Dr Napthine also listed changes to Victoria's taxation system and increases in the size of the police force as key highlights in his career.

Other career highs included being elected to Parliament in 1988 and being sworn in as the state's 47th premier on his birthday.

On Twitter, #memoriesofdenis was trending throughout the morning, as journalists paid tribute to the former premier's fondness for a "cheesy photo op".

Denis Napthine leaves politics with 'no regrets'

The lows included being dumped as opposition leader in 2002 and presiding over a government that became the first one-term administration in Victoria in almost 60 years.

But Dr Napthine said he would leave the Parliament with no regrets.

"I don't have any regrets during my time as premier," he said.

"I came in to be premier about 18 months out from an election, in challenging circumstances, and each and every day I got up enthusiastic, positive, doing my absolute best for the people of Victoria.

"There's a fair bit in life and in politics you can say 'woulda, shoulda, coulda', but you deal with the cards that are dealt to you, and it was a unique opportunity to become premier in those circumstances at that time."

Dr Napthine said he did not believe the controversial East West Link road project was to blame for the Coalition's 2014 election loss.

"Clearly the best option for the west of Melbourne is not the West Gate Distributor which [Labor] took to the election, which was a dog and is still a dog," he said.

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"The Western Distributor might be a slightly better bred dog but it's still a dog. What they should look at is the western section of the East West Link."

He would not be drawn on whether the Abbott government's poor polling in Victoria influenced the election result.

"I think that Tony Abbott has been the first to admit that they need to work harder as a government," he said.

Dr Napthine said he had thoroughly enjoyed life as an MP and planned to spend more time walking on the beach at Port Fairy, and enjoying family time.

"I bow out of parliamentary life with many happy memories, with lifelong friends and, hopefully, a record that says I made a difference to this state," Dr Napthine said.

'I look back with pride': Terry Mulder

Former public transport and roads minister Terry Mulder is following Dr Napthine into retirement.

He will leave this week after a 16-year parliamentary career.

"I look back with pride at having had the opportunity to serve the people of the Polwarth electorate, and having served as a minister in the Baillieu/Napthine governments," Mr Mulder said.

Denis Napthine and Terry Mulder looking at a map of free CBD trams in 2014. ( ABC News: Alison Savage )

The Liberal Party is due to pre-select a new candidate on September 20 in Dr Napthine's south-west electorate, with a by-election expected to follow soon after.

There will also be a by-election in the Polwarth electorate in western Victoria.

Earlier, Opposition Leader Matthew Guy paid tribute to his predecessor Dr Napthine.

"Denis is a friend, a colleague and an inspirational politician," he said.

"Every time I have visited him in his seat I have always admired how proud Denis is of the south west and of his lifelong connection to this part of Victoria.

"I have no doubt that he will remain a huge advocate for its future."

The departure of the two veteran Liberal MPs will trigger two by-elections in the neighbouring seats of South West Coast and Polwarth.

Warrnambool Mayor Michael Neoh has nominated for pre-selection for South West Coast, while local businessman Richard Riordan confirmed he would nominate for the seat of Polwarth.