Essentially the question: "If there are other intelligent beings in the Universe, why aren't they here?" After the discovery of alien races this was rephrased as "Why haven't such civilizations that did appear continue to expand until they colonized the entire galaxy?"
The Fermi Paradox puzzled terragens since the Atomic Age. Since it is quite possible for a technological, space-faring species to spread across the galaxy in less than 10 million years, or otherwise change things on such a large scale that it would be very visible (Megascale Engineering), the lack of such evidence was puzzling. We now know that many alien civilizations have existed in the past, and some still continue to exist, and have even joined Terragen Civilization (To'u'l, Limners, and others). But the question remains, why haven't such civilizations continued to expand, to colonize the entire galaxy?
Prior to the discovery of alien ruins during the Federation period, and then of actual races, various suggestions were offered by terragens, including: xenosophont life doesn't exist, other technological civilizations don't exist, other civilizations use communications methods outside the radio spectrum (i.e. lasers, neutrino beams, tachyons etc), other cultures don't have any interest in communicating, terragen space is part of a "wildlife preserve", a "prime directive" forbids aliens from interfering with younger civilizations, civilizations destroy themselves before or soon after becoming capable of communicating, they transcend and become incomprehensible, they undergo an inexplicable catastrophic collapse, berserker societies frighten the others so they hide and avoid broadcasting, or an inhibitor civilization exists which destroys others when they reach a certain level of development.
Some of these explanations have been completely disproved (e.g. the "wildlife preserve", "prime directorate", intimidating berserker societies, etc), others (non-technological society, reclusive, non EM-communication) have been shown to be valid but only to apply to a few races. Evidence of numerous extinct civilizations which expanded, flourished, and then vanished has encouraged belief in the inhibitor hypothesis, like the fabled Dawn Hunters, but even here evidence remains controversial, and many sapients fail to see how such a civilization - even if it did try to invade - could possibly faze the Archailects, who have abundant clarketech at their disposal. Other explanations include the Ginnungagap_Theory and Transcendent Burn-out. Even now, today, the Fermi Paradox remains as much a mystery as ever.
[after physicist Enrico Fermi]