But there are numerous threats to the American, especially from the new generation headed by Australia's world number one Ashleigh Barty and defending champion Naomi Osaka.
AFP Sport picks out five women to watch in Melbourne.
Will this be the moment when the American great finally makes it a 24th Grand Slam title?
The 38-year-old Williams, now a mother, has been stuck on 23 major triumphs since winning the Australian Open in 2017 when she beat her sister Venus.
Incredibly, Williams has lost her last four Slam finals, and each time failed to even win a set. Nevertheless, she is still a formidable presence and the woman to beat in Melbourne.
Now in her fourth decade on the WTA Tour, Williams started the season well when she won in Auckland last week -- her 73rd tour victory, and her first since the 2017 Australian Open.
The 22-year-old hit the highs and the lows in 2019.
When Osaka triumphed at last year's Australian Open for her second Grand Slam title, she looked set to reign over the women's game.
But the Japanese then endured a slump, exiting in the first round of Wimbledon and seeing her US Open defence fall flat.
Serena Williams, Wozniacki march into Auckland semis
With her father standing in as her coach, Osaka roared back to the form that made her number one with back-to-back titles in Japan and China.
In December she hired Belgian Wim Fissette as her coach -- her fourth in less than a year.
Australia's world number one will enjoy strong backing from the home crowd in Melbourne, but whether she thrives or shrinks in the spotlight will be key to her chances.
The 23-year-old, who once had a break from tennis and played professional cricket, won her maiden Grand Slam at the French Open in 2019.
Barty surged to the top of the rankings in June and has stayed there ever since, and sealed a breakthrough year with victory at the season-ending WTA Finals.
However, she lost to American qualifier Jennifer Brady in Brisbane last week in her first match of the year and the pressure to deliver for Australian fans will be immense.
The 28-year-old Halep will have to dispel lingering doubts about her troublesome back.
She is a former number one and two-time Grand Slam champion -- at Roland Garros in 2018 and then last year at Wimbledon, where she convincingly defeated Williams in the final, 6-2, 6-2.
Serena Williams faces Jessica Pegula in Auckland final
But Halep struggled towards the end of the year with her back, which has troubled her for several years. In December was voted WTA Fan Favorite for the third time in a row.
Just 15, the American ploughed through qualifying and then stunned five-time champion Venus Williams in the first round at Wimbledon last year, before going out in the fourth round to eventual champion Halep.
It was no fluke. Gauff went on to make the US Open third round and won her maiden title in Linz in her next tournament.
At the end of 2018 she was ranked 686th in the world, but 12 months later had rocketed up to 68th. Expectations are high for this star in the making.
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