One night only on July 21, Paula Poundstone visits the Levine Center for the Arts’ Knight Theater, 430 S. Tryon St., to perform her unforgettable stand-up comedy. Poundstone has served up decades of hilarity through radio, television and writing, but says stand-up is her truest medium.

“I consider myself a proud member of the endorphin-production industry, and I certainly get a contact high from being there,” Poundstone told qnotes. “Being in a room full of people who come out to laugh for the night is just such a treat.”

Known for a keenly reactive wit during her regular appearances on NPR’s weekly program “Wait, Wait — Don’t Tell Me,” Poundstone’s stand-up is largely driven by her audience.

“My favorite part of the night is talking to the audience. I kind of let that steer what direction I’m going in,” she said. “So the show’s different on different nights. And I’ll tell you my act is largely autobiographical.”

This autobiographical quality has served her well through the written medium. Poundstone’s recent book, “The Totally Unscientific Study of the Search for Human Happiness,” is a humorous memoir of sorts.

On the day of its release, the book found its way to the Top 10 on Amazon’s Best Sellers Humor Hardcover list as well as making the number one spot for Humor CDs. The back cover features praise from comedy legends like Dick Van Dyke, Dick Cavett, NPR’s Peter Sagal, and many more.

“A remarkable journey,” Tony and Emmy Award-winner Lily Tomlin said of the book. “I laughed. I cried. I got another cat.”

Lily Tomlin, who married her wife in 2013, is not Poundstone’s only LGBTQ fan. In fact, Poundstone’s work has long appealed to people disenfranchised by many popular comedians. She says that recognizing those people was a memorable moment in her career.

“I remember thinking, this was back when I was 20, that there were whole communities of people that couldn’t go out to be entertained without feeling — you know, without having really thick skins,” she said. “I didn’t want that to be the case in my [act].”

Still interested in appealing to this loyal demographic, Poundstone occasionally references LGBTQ issues in her act. When she’s not telling stories or talking with the crowd, she may take up current events. She once poked fun at North Carolina’s notorious HB2 at a show in Texas, where another bathroom bill was up for debate.

“I did this joke about the North Carolina bill …they did have sort of a squirrely response,” she said. “Some audience members that I was talking to afterwards, they said ‘oh yeah, we’re doing that here.’ And I’m like, oh, that explains a lot. I’m sorry to hear it.”

Poundstone was very open with qnotes regarding the “foolish” HB2. She commented that, though some performers opted to boycott the state in protest, she decided against it.

“My feeling was, a) me boycotting North Carolina would mean nothing, and b) I wanted the chance to talk to people.”

A true people person, Poundstone thrives on the energy of her crowd. Whether in live stand-up or on the radio, she tends to prefer witty exchange to fully-scripted jokes. That’s why, on her new weekly podcast launching on July 8, a studio audience was an absolute must.

The podcast, “Live from the Poundstone Institute,” is produced by her longtime colleagues at NPR. She says one of the show’s central concepts — examining odd research studies — originated from her tenure with “Wait, Wait,” when host Peter Sagal would quiz participants on such studies.

“One time [the topic] was — oh, that women liked men who dance like John Travolta. I just was thinking, I need some illumination on that study. Where was it done? How was it done? Who came up with that idea?” Poundstone said.

“Paula Poundstone is the funniest human being I have ever known,” Sagal said of the podcast. “Air becomes funny having been breathed by her.”

Indeed, the accolades seem to support Sagal’s point. Not only recognized by NPR, Comedy Central included Poundstone in its list of the 100 Best Standup Comics of All Time, and she won the American Comedy Award for Best Female Standup Comic.

Poundstone’s performance at the Knight Theater on July 21 will be an event to remember. Though successful in writing and radio, the comedian’s passion for improvisational comedy comes through with every unique show.

“A lot of what I do is unscripted, but the truth is I think more than anything it’s just a matter of being comfortable over time,” Poundstone said. “The truth is we’re all unscripted all of the time.”