Lawyers estimate the long-awaited trial will last four to eight weeks. Much of that time is expected to be spent picking a six-person jury that can be open-minded despite extensive publicity about some of the explosive issues, including racial profiling and self-defense, surrounding the case.
"They're going to have a tough time picking a jury. At this point who doesn't know who Trayvon Martin is and who George Zimmerman is," said David Weinstein, a former state prosecutor and criminal defense lawyer.
Zimmerman, a 29-year-old former neighborhood watch volunteer, faces up to life in prison if convicted as charged of second-degree murder.
More than 200 journalists have signed up to cover the trial and a tight blanket of security will be enforced by federal, state and local police in and around the courthouse in this town near Orlando in central Florida.
Even spectators in barricaded "public assembly zones" on the courthouse lawn will be subject to search. Four seats inside the courtroom will be rotated among local pastors who will monitor the trial and be ready to help calm any racial tensions.
The trial is being heralded as either a defining moment in the annals of civil rights, or an anti-climactic resolution of another senseless killing in gun-happy Florida.
Zimmerman, who is white and Hispanic, was the self-appointed neighborhood watch captain in a gated community of Sanford at the time of the killing on Feb. 26, 2012. Martin, 17, was a student at a Miami-area high school and a guest of one of the homeowners.
He was walking back to the residence after buying a bag of Skittles candy and a can of iced tea from a nearby convenience store when he died with a bullet in his chest during a struggle with Zimmerman.
Assistant State Attorney Bernie de la Rionda says Martin would be alive today but for the fact that Zimmerman, who profiled him as "a real suspicious guy," disregarded a police dispatcher's advice against pursuing Martin and wound up fatally confronting him.
Sanford police initially declined to arrest Zimmerman who claimed self-defense, saying they had no choice in light of Florida's controversial Stand Your Ground law, which allows anyone in fear for their life to shoot rather than retreat. But many saw the lack of an arrest as a symbol of second-class treatment of black victims in the criminal justice system.
Zimmerman was arrested only after a national outcry from both ordinary citizens and the nation's top civil rights leaders, and the appointment of a special prosecutor to take over from local law enforcement when it lost credibility. Almost 2.3 million people signed an online Change.org petition - still the largest petition in the organization's history - demanding "Justice for Trayvon Martin."
As the trial opens, Martin family lawyer Ben Crump said many are still waiting to see whether the family receives equal justice.
"I honestly think this is a civil rights/equal justice issue because everybody in the world is watching to see if everybody in America gets equal justice," Crump said. "This family has wanted to have their day in court. They wanted to not have their son's death be in vain. They pray continuously that the justice system does not fail them."
Others believe the injustice was cured once an arrest was made, and that now, regardless of the ultimate verdict, justice is being served.
"What this community wanted was for George Zimmerman to be arrested, the police chief to be fired and the state attorney to be gone. And all of this has been done," said Francis Oliver, one of Sanford's long-time civil rights leaders.
"We called it a victory when we got the arrest. But the call was for justice. I don't think we want someone to go to jail if we don't have the evidence," said Derek Turner, spokesman for the NAACP.
Prominent Orlando defense lawyer Mark Nejame suggests viewing the case through separate moral and legal lenses.
"Morally, I think it never should have happened," Nejame said. "I think that George Zimmerman was somewhat of a zealot in his effort to protect and serve and he should never have been following anybody when he was carrying a gun."
Legally, the case would depend on what the jurors believe happened in the struggle in the moments before the killing, he said.
Key points to watch as the trial unfolds will include testimony from a young woman, known as Witness 8, who was talking to Martin by cell phone in the last minutes of his life.
She has already gone on record describing Martin as scared and trying to get away from Zimmerman, as he pursued him. She has also said she last heard Martin say, "Why are you following me," after which she heard what sounded like Martin falling. Then the phone shut off. (Additional reporting by David Adams. Editing by Tom Brown and Lisa Shumaker)