Francis, 87, began on Monday a 12-day, four-country, two-continent odyssey.
Pope Francis on Monday embarked on his 45th and most ambitious trip of his papacy, both in terms of distance and duration.
It's a 12-day, four-country, two-continent odyssey; with stops in Indonesia, Papua New Guinea, Timor-Leste and Singapore.
This is not his first journey to the region: Early in his pontificate, he made four long-distance trips to South Korea, Sri Lanka, the Philippines and Japan. In more recent years he has also visited Bangladesh, Myanmar, Thailand and, last year, Mongolia.
The historic voyage comes amid recent concerns regarding his health. The Pope suffers from mobility issues and has been repeatedly hospitalized with respiratory illnesses.
As he often does, on Monday he boarded the Papal plane in a wheelchair, using a lift. He later used a cane to walk down the aisle to greet reporters, but appeared to be in good spirits. Francis turns 88 in just three months; this marks the first time he's left Italy in almost a year.
In Indonesia, the world's most populous Muslim-majority country, the Pope's message will focus on interreligious dialogue and cultural plurality, according to the Vatican. Francis will deliver remarks at Jakarta's famed Istiqlal Mosque, alongside Indonesia's Grand Imam.
Later the Pope will visit the "Tunnel of Fraternity" linking the mosque to a nearby Catholic church. The underground lane was recently built as a symbol of religious harmony.
On the eve of this departure, Pope Francis appealed for "concrete commitment" to tackle climate change. Francis will also travel to more remote parts of the country to meet with missionaries. According to Vatican spokesperson Matteo Bruni, some of the trip's other themes include social and technological development, as we well as the environment and the need to combat climate change.
In Papua New Guinea, one of the world's poorest countries, Pope Francis will stop in Port Moresby, one of the most dangerous cities in the world.
The Pope will then head to Timor-Leste, Asia's newest country, where he'll be confronted with the aftermath of another clergy sex abuse scandal. The Pope's first visit to the country comes just two years after the Vatican sanctioned independence hero Bishop Carlos Ximenes for having sexually abused young boys.
Many in the deeply Catholic country have brushed aside the allegations, choosing instead to continue celebrating the Nobel Peace Prize winner as a figure who saved lives during the country's bloody struggle for Independence. It's unclear if Francis will address the issue or meet with some of the victims, as he has in the past in other countries.
And in Singapore, the Pope will again focus on how different religions can live in harmony.
"Pope Francis will especially meet young people engaged in interreligious dialogue, entrusting them with the future of this path, so that they may become protagonists of a more fraternal and peaceful world," Cardinal Piero Parolin told Vatican Media,
His trip to Singapore is also widely seen as an attempt to improve ties with China, a constant diplomatic push by the Vatican over recent years, in the hope of improving circumstances for Catholics in China. The Pope has previously said it is his dream to visit the country. Three-quarters of the city state's population of Singapore are ethnically Chinese, and Mandarin is one of four official languages.