The launch team began loading more than a half-million gallons of fuel into Endeavour at dawn, moments after royal wedding vows were exchanged across the ocean between Prince William and Kate Middleton in London.
Commanding Endeavour on NASA's next-to-last shuttle flight is Navy Capt. Mark Kelly, who is married to Rep. Gabrielle Giffords. She was to watch the launch from Kennedy Space Center. Giffords was shot in the head in January and left rehab behind to attend the afternoon liftoff.
President Barack Obama also will attend with his wife and two daughters -- the first time in NASA history that a sitting president and his family will have witnessed a launch.
Launch time was 3:47 p.m. Forecasters put the odds of good weather at 70 percent; low clouds and stiff crosswind were the main concern.
Endeavour is bound for the International Space Station.
For its last hurrah, it's carrying one of the most expensive payloads in NASA's 30-year shuttle history: a $2 billion particle physics detector that will seek out antimatter and dark energy across the universe. Many in and outside NASA say the experiment, if successful, could validate science operations at the decade-old orbiting lab.
Kelly and his all-male crew -- all six of them space veterans -- saw their families for the last time, face to face, Thursday. They awoke a little before sunrise Friday as launch controllers gathered for the fueling operation.
"Watched 'Patriot' with the crew. Bonding before a big day," pilot Gregory Johnson said in a Twitter update late Thursday.
As the sun rose, recreational vehicles already lined the Banana River to the south, with a wide open view of the launch site.
As many as 750,000 people were expected to crowd nearby coastal communities. For days, police have been warning of massive traffic delays. Schools planned to dismiss early.
The space center itself, meanwhile, was bracing for 45,000 guests, including more than three dozen members of Congress, at least two former NASA administrators, and a score of high-level academic and space industry officials. The California Science Center in Los Angeles -- Endeavour's retirement home -- also was going to be represented.
NASA is ending the shuttle program this summer, after one last trip by Atlantis. Obama has put the space agency on a path to asteroids and Mars, ultimately, while encouraging private companies to take over Earth-to-orbit operations.
In the meantime, U.S. astronauts will keep using Russian Soyuz rockets to get to the space station.
Once Atlantis flies, it will be at least three years before America launches astronauts from their home soil again.
AP Science writer Seth Borenstein contributed to this report.
NASA site for Endeavour mission: http://www.nasa.gov/mission_pages/shuttle/shuttlemissions /sts134/index.html