Like Piercy's earlier novel Woman on the Edge of Time (1976), He, She, and It also examines themes such as gender roles, political economy, and environmentalism.

Dominated by powerful corporations known as "multis," the region includes environmental domes, independent "free towns," and the chaotic "Glop," where most Norikans live in violent, polluted conditions ruled by gangs and warlords.

When the protagonist, Shira, loses custody of her son Ari to her ex-husband Josh, she returns from her multi, Yakamura-Stichen (Y-S), to her hometown Tikva (Hope in Hebrew) - a Jewish freetown.

There, she starts working on the socialisation of the cyborg Yod (the tenth letter in Hebrew and a symbol for God in Kabbalah), who has been created illegally by Avram to protect the city.

In the next phase, Shira, Yod, Nili, and Gadi enter the Glop, connecting with an underground group where they discover Riva alive and involved in resistance activities.

Back in Tikva, Shira's family experiences a brief respite before Y-S invites them to a net meeting, demanding Yod for its technology.

Finally, Malkah leaves Tikva with Nili to visit a secret town in post-nuclear holocaust Israel and to profit from the possible biotechnological enhancements.