The easing guidance is a major step toward resuming life pre-pandemic -- but is likely to open the door to confusion.
Here is everything to know about the eased masking guidelines.
Where can fully vaccinated people take off their masks?
This new guidance clears the way for reopening workplaces, schools and other venues.
They can participate in most indoor and outdoor activities -- large or small -- without wearing a mask or physically distancing, said Dr. Rochelle Walensky, the director of the CDC.
She said those who are not fully vaccinated should continue to wear masks indoors. That's because of continued uncertainty about whether the vaccines can rev up a weakened immune system as well as they do normal, healthy ones.
Do fully vaccinated people need to wear mask on planes? Airports? Buses? Train stations?
The requirement to wear masks during travel -- on buses, trains, planes and public transportation -- still stands, Walensky said, and guidance for travel will be updated as science emerges.
Where else will mask-wearing still be required?
The new guidance still calls for wearing masks in some crowded indoor settings, specifically hospitals, prisons and homeless shelters. The CDC has not specified which other places should require fully vaccinated people to keep their face coverings.
People who are immune-compromised should speak with their doctors before giving up their masks.
How will businesses prove that customers were vaccinated?
That's unclear and will likely cause confusion.
There is no surefire way for businesses or others to distinguish between those fully vaccinated and those who are not.
Stopping people at the doors of the grocery store or bowling alley to check for a vaccine card probably won't work, Dr. Anthony Fauci said.
"I think there's going to be a pushback against questioning somebody when they walk in, because you can never validate or prove that they're telling you the truth," Fauci said.
And questioning people would be "virtually a functional equivalent of a vaccine passport, and I don't think that's going to work," he added.
In Florida, for example, Gov. Ron DeSantis signed an order banning businesses from requiring customers to show proof of vaccination and prohibiting state agencies from issuing so-called vaccine passports that document COVID-19 vaccinations and test results.
Do I need to cover my face within state borders that have mask mandates?
According to the CDC, Americans -- vaccinated or not -- need to follow federal, state, local and tribal rules and regulations, including local business and workplace guidance.
What else are fully vaccinated people allowed to do?
Along with loosened guidelines on mask-wearing and social distancing, the CDC announced that fully vaccinated people can:
- Resume domestic travel and refrain from testing before or after travel or self-quarantine after travel
- Refrain from testing before leaving the United States for international travel (unless required by the destination) and refrain from self-quarantine after arriving back in the United States
- Refrain from testing following a known exposure, if asymptomatic, with some exceptions for specific settings
- Refrain from quarantine following a known exposure if asymptomatic
- Refrain from routine screening testing if feasible
Walensky said science, not political pressure, prompted the CDC to change its guidance.
She said in the last two weeks, COVID-19 cases have dropped by one-third, and now, adolescents between the ages of 12 and 15 are eligible for the Pfizer shot.
She also cited studies -- one from Israel and one from the United States -- that show vaccines work.
"We have had a coalescence of more science that has emerged just in the last week," she said. "One is the effectiveness of the vaccines in general in real-world populations. One is the effectiveness against variants, which was just published last week. And then the effectiveness in preventing transmissibility."
The Associated Press and CNN Wire contributed to this report.