The show attempts to approach broad, difficult topics such as "time" and "morality" in an accessible and light-hearted manner and with a distinctive audio production style.

The original version of Radiolab was a three-hour weekly show on New York City radio station WNYC's AM signal.

[6] These early themed episodes were not necessarily science-related, but tackled issues such as the death penalty, religious fundamentalism and politics in Africa and the Middle East.

[11] They began evolving the show into its current form,[12][13][14] and by January 2004, Radiolab had become an hour-long, science-themed program characterized by Abumrad's unique sound design style.

The change was noticeably marked by the omission of NPR's name in the show's opening audio sequence after the tagline, "You're listening to Radiolab...from WNYC.

"[6] In addition, previously recorded interview segments are interspersed in the show's live dialogue, adding a layered, call-and-response effect to the questions posed by the hosts.

"[6] And unlike traditional journalism, in which the reader is given only access to the final article, not the interview, Abumrad added that Radiolab's process is more transparent.

[26][27] Radiolab also received a 2007 National Academies Communication Award "for their imaginative use of radio to make science accessible to broad audiences".

[29] In a 2007–2008 study by Multimedia Research (sponsored by the National Science Foundation), it was determined that over 95 percent of listeners reported that the science-based material featured on Radiolab was accessible.

[30] On September 24, 2012, in a podcast titled "The Fact of the Matter", the program ran a segment about the yellow rain incidents in Laos and surrounding countries in the 1970s.

After hearing the segment, Kao Kalia Yang and others complained that her uncle's viewpoints had been dismissed or edited out, that interviewer Robert Krulwich had treated them callously, and that the overall approach to the story had been racist.

The complaints prompted several rounds of allegation, apology, rebuttal, and edits to the podcast, as well as commentary in various sources such as the public radio newspaper Current.

[33][34] The program had been criticized for appearing to condone the actions of extremist groups, with Turner condemning the reporting as "abhorrent and irresponsible" for describing the vandalism and harassment they had been subjected to as "a really encouraging story" and "comforting.

"[35] In spring 2011, Krulwich and Abumrad took the show on a live, national tour, selling out in cities such as New York, Seattle, and Los Angeles.

[36] The tour covered 21 cities and primarily focused on a speculative fringe theory regarding the Cretaceous–Paleogene extinction event that has not been published in a peer-reviewed journal.

[38][42] The team working on the podcast became interested in the topic after studying an adoption case related to the Indian Child Welfare Act.