The source of The Plague (or Manslaughter, Gendercide and Le Grand Depart) that wiped out every living mammal with a Y chromosome except Yorick Brown, Ampersand and Doctor Matsumori is never fully explained. A number of explanations were given throughout the course of the book but the reader must decide which was the definitive answer. Discussing the cause of the plague, Vaughan is quoted as saying:
"I feel that there is a definitive explanation, but I like that people don't necessarily know what it is. In interviews we always said that we would tell people exactly what caused the plague. The thing was, we never said when we were going to tell. We weren't going to tell you when we were telling you, I should say. We might have told you in issue #3. There might have been something in the background that only a couple people caught. It might have been Dr. Mann's father's very detailed, scientific explanation. It might have been Alter's off-the-wall conspiracy theory. The real answer is somewhere in those 60 issues, but I prefer to let the reader decide which one they like rather than pushing it on them."
However, one of the explanations is more probable than all others when you take into account the fact that the only three males on Earth who survived the Gendercide were Yorick, Ampersand and Doctor Matsumori, and the only common thread linking all three was Dr. M's research:
As described in the "Motherland" story arc, the Y-chromosome had been "rationally self-destructing for hundreds of millions of years" and thus the birth of Dr. M's first successful human clone "triggered a time-bomb that had been ticking for a millennia," in other words the moment the Y-chromosome became obsolete "nature righted its course." Moreover, Doctor Matsumori had also discovered a "chemical compound that had an adverse effect on the genome of cloned mammals" which he injected into a capuchin monkey (Ampersand) in an attempt to kill his daughter's unborn clone fetus with a form of morphic resonance. Yet, as fate would have it, Ampersand was misdelivered to Yorick and when the plague struck, the compound ended up having the opposite effect on non-cloned mammals, shielding all three of them from "god's wrath."
Other less likely explanations put-forth in the book include:
- The Culper Ring, who may have created a chemical agent designed to prevent women from conceiving male children. This agent was introduced into China to cripple their economy, however, something went wrong, and the chemical agent instead killed males of all ages.
- The moment the plague struck, Agent 355 removed the sacred Amulet of Helene from the nation of Jordan. The amulet carried a warning that if it was ever taken from its homeland, it would create a tragedy greater than the Trojan War. It is also suggested that the wedding ring Yorick bought for Beth may have protected him from the effect of this curse.
- The Earth cleansing herself of the Y chromosome, as believed by the Amazons.
- The Rapture taking all men and leaving women as a punishment for original sin, as believed by an air traffic controller.
- The remaining (female) members of Sons of the Arizona were convinced that the government was responsible for the plague, and the top government leaders were lying in wait to take over the country.
- Changes in the Dreamtime impacting normal reality, as believed by some Australian aboriginals and Beth.
- One member of the "Fish & Bicycle" traveling theater troupe advanced the theory the plague was a direct response to the exclusion of women from true parity in the performing arts, thereby upsetting the natural order. In support of this theory, it was speculated the total exclusion of women from the stage in Shakespeare's day had resulted in pandemic outbreaks of the Bubonic Plague.
- At one point, the characters discuss the possibility that the release of the film The Divine Secrets of the Ya-Ya Sisterhood shortly before the plague may have caused a massive "death-by-chick-flick."