This tale of two families is set on a grand scale, as James Thomas Flexner brings his talents to bear on his own noteworthy heritage. An American Saga is an historical narrative, grounded on documentary sources, which ends with the marriage of Helen Thomas and Simon Flexner. The account deals equally with the lives and the backgrounds of husband and wife, the author's parents.

Simon Flexner was the famous medical investigator, discoverer of the "Flexner vacillus" and the "Flexner serum," who became the creating director of the Rockefeller Institute for Medical Research (now Rockefeller University) and eventually acknowledged leader of American medical science. The Kentucky-born son of impoverished German Jewish immigrants, he grew up in penury. As he never completed the eighth grade, he was almost completely self-educated when he appeared at the Johns Hopkins University before its celebrated medical school had been founded. Almost instantly he began making the discoveries that soon made him the leading younger medical scientist in the United States.