Regeneration is set in Craiglockhart War Hospital in the months July to November 1917. Some of the characters are real people: Drs Rivers, Bryce and Yealland, Dr Henry Head, and the poets Siegfried Sassoon, Wilfred Owen and Robert Graves. Barker blends fact and fiction as she focuses on their roles in the hospital against a backdrop of WWI. The themes in the novel look at the tensions that the war raised and the questions that were asked about authority, duty, class and gender, and homosexuality in an era when it was unlawful.

The novel begins with a reading of Sassoon's 'A Soldier's Declaration', and Rivers discussing Sassoon's motivations for writing it. Then Sassoon arrives at the hospital and the plot concentrates on the relationship that builds between Rivers and Sassoon, and Rivers and his other patients. Rivers' anthropological background is reflected in his approach to treating his patients - he engages with them over a period of several weeks (the average treatment times were two to four months) in order to understand the way in which they thought and to establish what it had been in the battle situation that had triggered a breakdown.

The novel also tackles the issue of homosexuality in Britain at that time. Rivers (in the novel) believed that it was despicable to use a man's private life against him in any way. Homosexuality was illegal in Britain from 1885 until 1967. Rivers and Sassoon discuss homosexuality as well as 'comradeship', the latter being a mechanism used by soldiers for bonding and coping with the stress of war.