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Rachni Wars
The Rachni Wars were a series of conflicts beginning in around 1 CE, when an expedition from the Citadel races activated a dormant mass relay. This relay opened a route to territory controlled by the rachni, a species of highly intelligent space-faring hive-minded insects. The rachni were alarmingly powerful, having massive strength in numbers, and extremely hostile. Negotiation with the rachni was impossible; their leaders, the rachni queens, dwelt in deep underground nests on worlds so hostile no one could survive them.
This period saw the Citadel races fight a losing war against the rachni for nearly a century until the salarians "culturally uplifted" a new species, the krogan. The volatile krogan homeworld, Tuchanka, had been ravaged by a nuclear winter caused by a krogan civil war. The salarians helped the krogan by giving them advanced technology and relocating them to a planet not cursed with lethal levels of radiation, toxins or deadly predators.
The true purpose of this salarian altruism soon emerged; the krogan were needed in the Rachni Wars as reinforcements. Unlike most Citadel species, the krogan had an extremely rapid breeding cycle. They had not only the numbers to drive the advancing rachni back, but the ability to endure the harsh conditions of the rachni planets. The krogan pursued the rachni to their home worlds, descended deep underground to find the rachni queens, and systematically destroyed both the queens and their eggs. The Citadel Council would normally have objected to such total destruction, but after centuries of relentless war, complete eradication of the rachni seemed the only possible solution.
In 300 CE, the rachni were declared extinct, bringing the Rachni Wars to an end. After that, it became illegal to open a mass relay without knowing where it leads, to avoid another such encounter.
It is postulated in Mass Effect 2 that another party, likely the Reapers, manipulated the rachni into starting the war. If Commander Shepard allowed the Rachni Queen to live in the first game, an asari acting in service to the rachni says that the rachni are not an inherently hostile race. Shepard can question her on what might have caused the rachni to attack upon their discovery by the Citadel races, and Shepard can suggest mind control. The asari is uncertain, but the Rachni Queen's description of how her race was forced to resonate with a "sour note" is reminiscent of Reaper indoctrination.