Lee's designated successor - Deputy Prime Minister and Finance Minister Heng Swee Keat - unexpectedly ruled himself out for the top job on April 8.
On Friday, (April 23), Lee announced a broad cabinet reshuffle and gave new portfolios to ministers who have been tipped as contenders for the top job.
Below are details of three of those men who have been identified as potential successors by political analysts and veteran members of the ruling People's Action Party.
LAWRENCE WONG, 48
Wong, who was named finance minister in the reshuffle, has gained a high profile as one of the public faces of Singapore's fight against Covid-19.
He broke into tears during a speech in parliament last year as he thanked healthcare workers and others for their efforts in tackling the pandemic, winning widespread public support.
He was praised for his communication skills when, as co-chair of a Covid-19 taskforce, he urged people to keep wearing masks and maintain social distancing.
Wong, who is currently education minister and the second minister for finance until the reshuffle comes into force on May 15, was previously the minister for national development, which oversees the real estate market and planning.
Wong studied economics at University of Wisconsin-Madison. He also attended the University of Michigan-Ann Arbor and the Harvard Kennedy School.
ONG YE KUNG, 51
Ong, who was named health minister in the shakeup, played a key role in reopening Singapore and negotiating reciprocal travel arrangements with other countries amidst the pandemic in his current role as transport minister.
He served as Lee's press secretary from 1997-2003 and his principal private secretary from 2003-2005.
In 2005, Ong took over as chief executive of the government's Workforce Development Agency, and three years later became deputy secretary general of the national confederation of labor unions.
Ong studied economics at the London School of Economics, also on a government scholarship. He later studied at the Institute of Management Development in Switzerland.
Ong was among a group of ruling party candidates defeated by the opposition in a 2011 election. While waiting to stand again, he worked as director of group strategy at Keppel Corp , which is owned by state investor Temasek Holdings, with businesses from rig building to property development.
He won a seat in 2015. He was previously education minister.
CHAN CHUN SING, 51
Chan, who was named education minister in the reshuffle, was tasked with keeping industries operate through Covid-19 curbs, in his current role as trade and industry minister.
Chan was raised in a single-parent household and comes from a more humble background than many peers. He is known for a down-to-earth manner.
Chan was awarded a government scholarship and read economics at Cambridge University and later studied at the Massachusetts Institute of Technology.
A government scholarship requires the recipient to go into public service after university and Chan spent 24 years in the military, rising to the rank of Chief of Army in 2010.
He entered parliament after a 2011 general election and was appointed acting minister for community development, youth and sports, and served in the communications ministry. He later served as minister for social and family development.
He was appointed Heng's deputy on the "fourth generation" leadership team in 2018. - Reuters