The radio show was conceived by Neil Denny and Richard Sanderson at a meeting in a pub beer garden in London Bridge on 7 July 2005.

The first episode aired on 2 September 2005 and featured a panel of a scientist (Sid Rodrigues), physicist and ex-born again Christian (Norman Hansen) and a folklorist (Scott Wood), along with Neil Denny and Richard Sanderson as the show's hosts.

It features a mixture of edited podcast interviews and original articles by writers including Jonathan Meades, Fergal Keane, Nick Cohen, Suzanne Moore, and more.

In July 2015, Miranda Sawyer, presenter of BBC Radio 4's In Pod We Trust, praised Little Atoms, writing "[Neil] Denny's modesty and well-informed interest enriches Little Atoms, and there are loads of shows to choose from (the As alone include Adam Curtis, Alex Cox and Aleks Krotoski).

"[7] Esquire magazine's Andrew Harrison described the podcast as "engaging, irreverent and unashamedly intellectual", making "Radio 4's Front Row sound like the E!