Lipshitz Six, or Two Angry Blondes details the peculiar history of the Lipshitz family, Russian Jewish refugees who narrowly survive the bloody Kishinev pogroms of 1903. Upon landing at Ellis Island four years later, Esther and Hersh Lipshitz discover their atypically blond-haired, blue-eyed, five-year-old son Reuven is missing. After a year-long, fruitless search for the boy in New York City, the Lipshitz family relocates to Texas, joining a relative already living in the state's dusty panhandle.

Over two decades, Esther sporadically ponders the fate of her lost son, and when she first sees a photograph of the equally blond-haired, blue-eyed Charles Lindbergh after his 1927 transatlantic flight, she becomes convinced that the aviator is her son Reuven, now grown up. Esther's obsession with Lindbergh (Reuven) slowly destroys those around her and leaves far-reaching, insidious effects on the entire Lipshitz lineage.

New York City, 2002: Meet 30-year-old T Cooper—the last living Lipshitz, who has recently received in the mail an unsolicited box from his estranged mother in Amarillo, Texas. In it, he finds hundreds of clippings, photographs and letters related to Charles Lindbergh and his family, all once carefully preserved by T's great-grandmother Esther. When T is forced back to Texas to bury his suddenly deceased parents, he finds himself the sole inheritor of a family history filled with loose ends, factual errors, and decidedly maniacal behavior.

An ex-literary golden boy with a thriving career as a bar mitzvah entertainer who impersonates the rapper Eminem, T rages against the world in a struggle to make at least some sense of all that came before him, and—in light of his wife's persistent desire to have a baby—what legacy he might leave behind as well.