No agenda for the Kuala Lumpur Summit has been released, but it could address age-old disputes in Kashmir and the Middle East, the conflicts in Syria and Yemen, the plight of Myanmar's Rohingya Muslim minority, and mounting outrage over China's camps for Uighur Muslims in Xinjiang — a subject that will doubtless upset Beijing — as well as how to counter the spread of Islamophobia in the world.
Two of the world's most outspoken leaders, Malaysia's Prime Minister Mahathir Mohamad and Turkey's President Tayyip Erdogan will be giving their views during the four-day summit, which begins with a welcome dinner on Wednesday and wraps up on Saturday.
Pakistan's Prime Minister Imran Khan, who along with Dr Mahathir and Mr Erdogan had been a prime mover behind the summit, made a belated decision to skip the meeting.
Some Pakistani officials, unnamed because they are not authorised to speak to the media, said Mr Khan pulled out under pressure from close ally Saudi Arabia, though media reports say his officials deny that was the reason why the world's second largest Muslim country won't be represented.
Iranian President Hassan Rouhani and Qatar's Emir Sheikh Tamim bin Hamid Al-Thani, whose countries have tense relations with Saudi Arabia, are also attending.
Explaining its decision to stay away, Saudi Arabia said the summit was the wrong forum for matters of importance to the world's 1.75 billion Muslims, though some analysts suspected the Kingdom feared being diplomatically isolated by regional rivals Iran, Qatar and Turkey.
Saudi state news agency SPA reported that on a call with Dr Mahathir on Tuesday, Saudi King Salman reaffirmed that such issues should be discussed through the Organisation of Islamic Cooperation (OIC).
A Saudi source said Saudi Arabia was invited but would only attend it the meeting was held under the auspices of the OIC.
"They are very concerned about it," the source said of the summit, declining to be named as he was not authorised to talk to media.
The Saudi government's centre for international communication did not respond to a request for comment.
The absence of Saudi Arabia, the birthplace of Islam, whose king also hold the title of Custodian of the Two Holy Mosques in Mecca and Medina demonstrates some of the divisions in the Muslim world.
"The issue is that you've got blocs," said James Dorsey, a senior fellow at S Rajaratnam School of International Studies and Middle East Institute in Singapore. "You've got a Saudi-UAE bloc, Turkey-Qatari bloc, and Pakistan in the middle trying to hedge their bets."
Indonesia, the country with the world's largest Muslim population, would be represented by Vice-President Ma'ruf Amin, a cleric overseeing the country's fight against radicalisation and terrorism.
Even as delegations were arriving in Kuala Lumpur, Malaysian officials were unable to provide a final list of who would be attending. Mahathir's office said that invitations had been sent to all 56 OIC member states, but officials said only about 20 were sending delegations, and fewer would be led by heads of state.
Defending the summit, Mahathir's office issued a statement saying there was no intention to create a "new bloc as alluded to by some of its critics".
"In addition, the Summit is not a platform to discuss about religion or religious affairs but specifically to address the state of affairs of the Muslim Ummah," it said, using the Arabic term for community.
Speaking to Reuters last week, Dr Mahathir expressed frustration with the OIC's inability to forge a united front and act decisively. During that interview, the Malaysian leader also raised the possibility that the alleged mistreatment of Muslim Uighurs in China's Xinjiang would be discussed.
Beijing describes the camps where Uighur Muslims are being held as "vocational training centres", while critics say they are mass internment camps.