The easing guidance is a major step toward resuming life pre-pandemic -- but it opens the door to confusion as states, cities and businesses can dictate their own rules.
Here is what communities across the Delaware Valley need to know.
The City of Philadelphia will lift its outdoor mask mandate on Friday, May 21. This means masks will no longer be required at outdoor gatherings, restaurants, performances, and sporting events.
The indoor mask guidance will remain. It may be lifted for fully vaccinated people on June 11, but that depends on COVID cases and vaccination rates.
The Pennsylvania Health Department says it will follow the CDC's recommendation to ease mask-wearing for fully vaccinated people, allowing them to stop wearing masks outdoors in crowds and in most indoor settings.
The health department is stressing that this only affects those that are fully vaccinated.
"(Thursday's) guidance from the CDC affects only people who are fully vaccinated," Acting Health Secretary Alison Beam said. "This is another incentive to get the vaccine that is now easily and conveniently available. Once 70 percent of Pennsylvanians over 18 are fully vaccinated, we can completely lift the masking order."
The new CDC guidance still calls for wearing masks in crowded indoor settings like buses, planes, hospitals, prisons and homeless shelters, but it will help clear the way for reopening workplaces, schools, and other venues - even removing the need for social distancing for those who are fully vaccinated.
New Jersey's requirement for masks indoors will remain in effect, Gov. Phil Murphy said Friday.
Murphy has said that fully vaccinated people can forgo masks outside, but hasn't lifted an indoor mandate.
"We're frankly not there yet," he said.
The governor said it's "only a matter of time," perhaps weeks before the indoor mask mandate is lifted in New Jersey.
Some business owners Action News spoke with say keeping the masks on is fine with them.
"I haven't had anyone not want to wear a mask indoors. I think we're all used to it and it's ok if we take our time getting out of it," said Sarah McEwan
Elizabeth Yard, owner of Gail Force Winds shop and art studio in Bordentown, said she was planning on keeping a mask policy in her store, regardless of CDC or state guidelines.
Her shop holds art workshops for people living with disabilities, who are also at higher risk for complications due to COVID-19.
"As a business owner, how do you know who's vaccinated and not? I don't want to get into carding people," said Yard.
RELATED: What fully vaccinated people can, cannot do according to CDC's new mask guidelines
Governor John Carney on Friday announced that - effective May 21 - Delaware will lift its mandate and will follow guidance issued by the CDC for all indoor and outdoor activities.
In a statement, Carney said:
"The CDC guidance advises that fully vaccinated people can stop wearing masks in most places indoors and outdoors, except in crowded settings, including on public transit, planes, in schools, health care facilities and congregate settings like prison facilities and homeless shelters. On Friday, May 21, Governor Carney also will lift all remaining mask requirements outdoors.
"Those who are not fully vaccinated, including children not yet eligible for a COVID-19 vaccine, should continue to wear masks when around others who are outside their immediate household, according to the CDC guidance. Unvaccinated Delawareans ages 12 and older are urged to get vaccinated as soon as possible to protect themselves from infection and serious illness. Find a vaccination site: de.gov/getmyvaccine
"It's clear that the COVID-19 vaccines are extremely safe and protective against infection and serious illness," said Carney. "Delawareans who are fully vaccinated have significant protection against this virus and can feel comfortable getting back to the things they loved to do before this pandemic. For our neighbors who aren't vaccinated, the message is clear. The COVID-19 vaccine is the best protection we have against the virus. Getting vaccinated is the best way to protect you and those you love. In the meantime, Delawareans who are unvaccinated, including children, should continue to wear masks in public places."