Boris Rhein, the top security official in the German state of Hesse where the shooting took place, identified the shooter as a 21-year-old from Kosovo. Family members in Kosovo described the suspect as a devout Muslim, who was born and raised in Germany and worked at the airport.
In Washington, President Barack Obama promised to "spare no effort" in investigating the slayings.
"I'm saddened and I'm outraged by this attack," he said.
The attack came as the bus sat outside the airport's Terminal 2, according to Frankfurt police spokesman Manfred Fuellhardt. The bus driver and a passenger were killed, while one airman suffered light injuries and a second suffered serious wounds and was in life-threatening condition, he said.
The attacker and U.S. military personnel apparently had an altercation in front of the bus just before the man started shooting, Fuellhardt said. The attacker also briefly entered the bus, and was apprehended by police when he tried to escape.
The airmen were bound to Ramstein Air Base from where they were to have been deployed to support an overseas operation, the U.S. military said, without elaborating.
The U.S. has drastically reduced its forces in Germany over the last decade, but still has some 50,000 troops stationed here. It operates several major facilities in the Frankfurt region, including the Ramstein Air Base, which is often used as a logistical hub for operations in Afghanistan and Iraq.
U.S. Air Force Europe spokeswoman Maj. Beverly Mock said all four victims were airmen. They were based in Britain, a U.S. Air Force spokesman for the Lakenheath airfield in eastern England said.
Lakenheath is home to the 48th Fighter Wing, the only F-15 fighter wing in Europe. It employs some 4,500 active-duty military members, as well as 2,000 British and U.S. civilians.
In Berlin, German Chancellor Angela Merkel expressed sympathy for the victims and their families and pledged that Germany would do everything in its power to investigate the crime.
"It is a terrible event," she said.
The German news agency DAPD quoted Rhein, the security minister who rushed to the scene of the shooting, as saying there were no indications of a terrorist attack.
Still, a member of the U.S. House Homeland Security Committee, Rep. Patrick Meehan, said in Washington that it looked like a terrorist attack. The chairman of the subcommittee that focuses on terrorism and intelligence added he did not have all the facts yet and was still being briefed.
At Frankfurt airport, taxi cab driver Salimi Feraidon was sitting at a stand about 200 yards (meters) away when the attack took place and said it was over quickly as police rushed to the scene.
"We just heard the shots," he said.
Kosovo Interior Minister Bajram Rexhepi identified the suspect as Arif Uka, a Kosovo citizen from the northern town of Mitrovica.
"This is a devastating and a tragic event," Rexhepi said. "We are trying to find out whether this was something that was organized or what was the nature of the attack."
Kosovo remained part of Serbia amid the collapse of former Yugoslavia in the early 1990s, but a struggle for independence by ethnic Albanians there eventually led to the Kosovo war in 1998. The bloodshed was halted only in 1999 when NATO stepped in and bombed Serbia, followed by the deployment of peacekeepers. The NATO-led Kosovo Force still has some 8,700 troops there provided by 32 nations, including the U.S. and Germany.
The northern town of Mitrovica is best known for the ongoing ethnic division between majority ethnic Albanians and minority Serbs. The former mining town, however, also has been the focus of reports that it breeds radical Islamic extremists.
In the past, Western intelligence reports have said the region could be an ideal recruitment ground for the so-called "white al-Qaida" - Muslims with Western features who could easily blend into European or U.S. cities and execute terrorist attacks.
In Mitrovica, family members said the suspect's name was spelled "Arid" not "Arif," saying that he was born and educated in Germany where his family moved some 40 years ago.
Uncle Rexhep Uka said the suspect's grandfather was a religious leader at a mosque in a village near Mitrovica.
Rexhep's son, Behxhet, said he spoke to the alleged gunman's father, Murat Uka, several times by telephone from Frankfurt after the family had been contacted by Kosovo police, who told them that they only thing he knew was that his son did not come home from work on Wednesday.
Murat Uka did not answer calls to his home in Frankfurt.
A leftist terror group, the Red Army Faction, was also responsible for a string of attacks on Americans in the 1970s and 1980s before the group was disbanded in 1998.
More recently, German police thwarted a plot in 2007 to attack U.S. facilities by members of the extremist Islamic Jihad Union. Four men had planning to attack American soldiers and citizens at facilities including the U.S. Air Force's Ramstein Air Base in Germany but were caught before they could carry out the plot.
Baetz reported from Berlin. Pauline Jelinek in Washington, Nebi Qena in New Haven, Connecticut, Sylvia Hui in London, Visar Kryeziu and Sylejman Kllokoqi in Mitrovica, David Rising, Melissa Eddy and Geir Moulson in Berlin contributed to this report.