Vera and Irene reveal their exploits and adventures to each other in their letters, but sometimes their correspondence becomes fractious when one accuses the other of being an alcoholic or engages in too much one-upmanship. Other characters include Vera's gay son Howard who runs a sheep farm with his partner Anthony, and her daughter Karen; and Irene's daughter Lesley. Vera and Irene always strive to outdo each other, whether with their recipes, holiday destinations or who has the best grandchildren. Later in the show's run it is revealed that Irene also has a son called Christopher, who had been given up for adoption years previously.
The humour is mostly derived from the lack of insight of the two main protagonists, but there is also a somewhat melancholic theme that lurks just beneath the surface at the way these two women are taken for granted by their respective families. By the end of 2004's Ladies of Letters Spring Clean it is implied that there has been something of a parting of the ways between the women and their kith and kin. Linguistically, there is also the misspellings and many word errors in the two ladies' letters.
Ladies of Letters Go Global (broadcast January 2006) featured a somewhat bizarre and unlikely world tour undertaken by the two women, in contrast to the more naturalistic tone of previous stories. The BBC issued a CD collection of the first seven series as a special 'biscuit tin' release in October 2006 A short, newly-written, episode was featured as part of the Woman's Hour 60th Anniversary concert in October 2006.
Ladies of Letters Say No was broadcast in August 2007 and featured a broadly satirical take on the involvement of the private sector in the NHS, concentrating on the underhand dealings of the tycoon Alan Trumper. Ladies of Letters Go Green - the ninth series - was broadcast in March 2008