Its narrator is 65-year-old author Nathan Zuckerman, who appears in several earlier Roth novels, including two books that form a loose trilogy with The Human Stain, American Pastoral (1997) and I Married a Communist (1998).

[1] Zuckerman acts largely as an observer as the complex story of the protagonist, Coleman Silk, a retired professor of classics, is slowly revealed.

Coleman Silk is a former professor and dean of the faculty at Athena College, a fictional institution in the Berkshires of western Massachusetts, where he still lives.

In 1996, two years before the main action of the novel, Silk is accused of racism by two African-American students after he wonders aloud whether the reason they have missed all his classes so far is that they are "spooks".

Especially in the second half of the novel, there are scenes detailing the thoughts and feelings of other characters, notably Faunia, Les Farley, and Delphine Roux, Silk's main antagonist at Athena.

The Human Stain is set in 1998 in the United States, during the period of President Bill Clinton's impeachment hearings and scandal over Monica Lewinsky.

[2] Roth described in a 2012 piece for The New Yorker how his novel was inspired by an event in the life of his friend Melvin Tumin, a "professor of sociology at Princeton for some thirty years."

Tumin was subject to a "witch hunt" but was ultimately found blameless in a matter involving use of allegedly racial language concerning two African American students.

[4] Roth said he wrote the trilogy to reflect periods in the 20th century – the McCarthy years, the Vietnam War, and President Bill Clinton's impeachment – that he thinks are the "historical moments in post-war American life that have had the greatest impact on my generation.

Indeed, it closely parallels the story of Nathan Zuckerman, himself another dutiful, middle-class boy from New Jersey who rebelled against his family and found himself exiled, 'unbound' as it were, from his roots.

[2]Mark Shechner writes in his 2003 study that in the novel, Roth "explores issues in American society that force a man such as Silk to hide his background, to the point of not having a personal history to share with his children or family.

His downfall to some extent is engineered by Delphine Roux, the young, female, elite, French intellectual who is dismayed to find herself in a New England outpost of sorts, and sees Silk as having become deadwood in academia, the very thing he abhorred at the beginning of his own career.

[17][18] In choosing it for its "Editors' Choice" list of 2000, The New York Times wrote: When Zuckerman and Silk are together and testing each other, Roth's writing reaches an emotional intensity and a vividness not exceeded in any of his books.