The basic theme of The Gold Bug Variations is a question: What is the role of humankind in the universal scheme? Ressler went as far as he could to answer this question through understanding the physical components of human existence. He could not, however, move beyond the physical, and therein are found the seeds of his withdrawal from the world in which he had, as a twenty-five-year-old suggested the promise of an ability comparable to that of J. D. Watson and Francis Crick, who led the DNA research that resulted in the discovery of the double helix.

The novel's four main characters—Jan O'Deigh, Franklin Todd, Stuart Ressler, Jeanette Koss—have fallen short of the fulfillment usually linked with success. The two women are unable to bear children, which even liberated society, however reluctantly, views as women's fundamental function. Both men have voluntarily stopped short of their potential, Stuart by abandoning his university research and Franklin by discontinuing doctoral studies short of the degree he sought.

None of the characters appears to have significant regrets about what society might view as their failures. They go about living the lives they have carved out for themselves. Powers is searching for the answers to universal questions about the meaning of existence. Possibly this is his partial answer: Do not bemoan that which you are unlikely to attain.

Broadly speaking, the overall theme of the novel concerns the total meaning of existence. In his novels, Powers has consistently explored the meaning of life. He has explored in most of his work the roots of postmodern society.

To date, his conclusions about modern society have been tinged with pessimism. In The Gold Bug Variations, two men elect not to realize their potentials, and both of the women associated with these men are barren. Just as the men, by their own choices, do not bear professional offspring, neither can either woman bear human offspring.

Ironically, Stuart Ressler and his research team, having probed the origins of physical existence as they moved toward isolating the major building blocks of life, cannot understand the origins of the very consciousness that makes their exploration possible. According to Powers, that consciousness cannot understand its own origins.

Powers appears to suggest that although humans can move toward knowing, possibly even understanding, the real, physical world, they cannot so readily understand the more elusive nonphysical world that coexists alongside it. Powers has established a unique metaphysic in The Gold Bug Variations.

By positioning his novel in a time when the United States was seriously questioning its own values in terms of race, involvement in foreign conflicts such as the Vietnam War, and nationalism, he has set the stage for examining why some very promising people choose to withdraw from society rather than face it.