It will be a particularly poignant defence for home favourite Vincenzo Nibali with the Giro d'Italia celebrating its 100th race, but the ever-dangerous Nairo Quintana poses formidable opposition.
Twelve months ago, Nibali was celebrating at the top of the podium for the second time in his distinguished career for former team Astana.
The 32-year-old is aiming for a hat-trick of wins at the first of 2017's three Grand Tours, and we assess the main talking points ahead of the battle for the maglia rosa.
MORE HOME SUCCESS FOR NIBALI?
Nibali is a cycling legend and has won each of the three Grand Tours, including his two triumphs at the Giro in 2013 and 2016 - the latter thanks in part to an astonishing crash from Steven Kruijswijk on stage 19.
This year will hold particular importance for the Bahrain-Merida rider, with the Giro in its 100th edition and stage five finishing in his home town of Messina.
Nibali was keen to temper expectations at a news conference on Wednesday, saying: "Everybody knows what my ambition is. I want to be on the podium.
"It is not easy but each of us has worked in the right direction to come here with the best physical condition. We know we have to face high level opponents and we take this into account."
QUINTANA HAS THE CREDENTIALS
The winning rider at the Giro must be an adept climber, a dab hand in the time trials, and have the heart of a lion to battle the hazardous roads.
Quintana possesses all of those traits in abundance and it would be no surprise to see the cunning Colombian wearing the maglia rosa when he crosses the finish line in Milan on May 28.
The Movistar man proved his credentials by topping the podium in 2014, while he secured a second taste of Grand Tour glory by taking out the Vuelta a Espana last year.
Quintana does not have a great deal of racing under his belt this year, but can lay claims to victories at February's Volta a la Valenciana and the Tirreno-Adriatico in March.
TEAM SKY'S YEAR AT LAST?
The Tour de France has been dominated by Team Sky, whose policy of 'marginal gains' has seen them triumph in cycling's most famous race in four of the past five years.
It has been a different story at the Giro, though, with Bradley Wiggins' retirement with a chest infection in 2013 and Richie Porte's time penalty for an illegal wheel swap two years later among their disappointments.
However, in joint-team leaders Geraint Thomas and Mikel Landa Sky have two men with a point to prove.
Thomas has spent much of his time at Sky as a support rider to Wiggins and Chris Froome and will be desperate to prove he can a contender in his own right, while Landa is in the second of a two-year deal and keen to secure his future.
WHERE WILL THE RACE BE WON?
The Giro, which starts with three stages in Sardinia and two in Sicily before moving to the mainland for stage six, has four uphill finishes and a time trial in the opening 10 outings.
But it is the final gruelling week that will determine the winner.
A 12-kilometre climb to the finish line awaits on stage 14, while two rounds later the riders face a gruelling ascent up the famous Mortirolo.
Throw in five categorised climbs on stage 18 and a 15km uphill finish the following day and we will know who is on course for victory.
In total, 3,615km will have been covered from start to finish, ending with a near 30km individual time trial – the first time since 2012 the Giro has ended that way.
TRIBUTES TO SCARPONI
The Mortirolo climb will be dedicated to former Astana rider Michele Scarponi, who tragically died following a collision with a van at a crossroads near his home town Filottrano last month.
The rider who passes the Mortirolo first on stage 16 will be awarded double King of the Mountains points, while the pink caravan will also observe a minute's silence before the start of stage one.
"We still think the news we received as of something untrue," Nibali said of Scarponi, who was due to lead Astana in the absence of the injured Fabio Aru.
"It is hard to talk about it. We are still trying to understand this tragedy. It is hard to express thoughts and words."