Host nation Germany has billed the two-day G20 foreign ministers meeting in Bonn as a chance for the club of leading economies to discuss how to work together on challenges ranging from climate change to the Syrian war at a time of geopolitical upheaval.
But all eyes will be on America's top diplomat, whose maiden trip to Europe will bring him face-to-face with allies seeking reassurance that President Donald Trump will not upend decades of US foreign policy despite his fiery campaign rhetoric.
Here are the main issues the G20 foreign ministers are expected to discuss over the two-day meeting:
The first task for the G20 ministers, including Russia, China, Brazil and India, will be to get Tillerson to spell out exactly what "America First" means in practice.
For Trump, it is what it says - American interests come first and the United States will treat other nations on a come-as-you-are basis, doing specific deals on specific issues as it sees fit.
That means preserving the global order - built up since World War II based on the United Nations and international law - could be a thing of the past, leaving everyone in uncharted territory.
Trump's predecessor Barack Obama rallied US allies to impose a damaging series of sanctions on Russia over the Ukraine crisis and its annexation of Crimea in 2014.
But the new president has taken a much softer stance on Russia while his nomination of Tillerson, the former chief executive of oil giant ExxonMobil who is known for his close business ties with Moscow, caused unease.
Tillerson is due to meet Russian Foreign Minister Sergei Lavrov separately in Bonn.
The Ukraine crisis meanwhile remains unresolved, with fighting between government and pro-Moscow rebel forces flaring up again shortly after Trump's inauguration.
Revelations that Michael Flynn, who resigned on Monday as Trump's national security adviser, discussed sanctions with the Russian ambassador to Washington have also raised many questions over where Trump stands on ties with Moscow.
Trump caused outrage in Beijing when he talked by phone to the president of Taiwan following his election victory, seemingly ditching the "One China" policy on which the two countries have built ties since the 1970s.
It appeared at one stage that Chinese Foreign Minister Wang Yi would not attend the Bonn meeting, but it now seems he will after a conciliatory call between Trump and his Chinese counterpart Xi Jinping, reasserting the One China principles.
Trump also attacked China on the campaign trail, saying one of the US's biggest trade partners got by far the best of the deal and that had to change.
The prospect of any US unilateral trade protectionist measures would cause alarm, with many of the G20 states dependent on export-led growth.
NATO, European Union
Trump's dismissive comments about an "obsolete" NATO sparked deep concern among Washington's European allies who Obama had marshalled into the biggest military build-up since the end of the Cold War in response to a more assertive Russia.
At the same time, he praised Brexit, saying Britain would be better off outside a failing super-state EU as voters turned to national solutions and populist leaders.
Syria, Middle East
Trump's willingness to cooperate with Russia to fight Isis and other extremist groups has been picked up by Moscow, adding uncertainty to where Washington stands on the future of Syrian President Bashar al-Assad.
Obama insisted Assad had to go, but Moscow says he should stay and has stolen the initiative in hosting peace talks with key NATO ally Turkey.
As for the stalled Middle East Peace Process, the White House signalled on Tuesday it would no longer insist on the internationally backed two-state solution to the Israel-Palestinian conflict, which successive US governments have supported for nearly 50 years.
He said he would back a single state if it led to peace
By Bryan McManus, AFP