* When the Earth Defense Army is doing a data analysis on the recently unearthed Stone-Like in Scene 2, the moment they are about to see its memories [[OhCrap it decides to first blow up the 3rd Research Division]]. Cue (probably the Stone-Like) summoning an [[NothingIsScarier exponentially increasing number of objects around the complex]] while everyone inside is losing their minds!
* The last stretch of Stage 5 "Victim": while the tone of the game is rather sad, what with the crew of the ''Tetra'' being the last remnants of humanity and all, but the specific example is the moment [[spoiler:where Gai does his HeroicSacrifice]].
* In the epilogue, [[spoiler:C.R.E.A.T.O.R. is never able to tell the clones of Buster and Reana about the Stone-Like and change the future. All it did is create a StableTimeLoop; there's no guarantee [[ShootTheShaggyDog humanity can be saved]]]].
*** Unless one counts ''VideoGame/{{Ikaruga}}'' as a distant sequel set in the same universe...
** [[spoiler:Even if it could tell them]], [[{{HumansAreBastards}} when was the last time humans ever learned from their mistakes]]?
*** It happens [[HumansAreFlawed all the time]], actually. You'd be surprised at how much someone can change when under the threat of total annihilation if they don't reform.
* The game's premise itself, particularly how it might feel being one of a few {{Sole Survivor}}s of a race left in the universe in a spaceship that barely escaped the DepopulationBomb, knowing you're all that's left and next-to-nothing about what caused it to happened in the first place. At the same time, you realize you'll have to return to the planet in a year or so when you run out of supplies. A few humans simply isn't enough to repopulate the human race, thus even if you manage to destroy the ArtifactOfDoom, there will be nothing but a dead, hopeless planet left.
* The fact that '''[[DownerEnding nothing good came out of this entire story]]''': it's all a hopeless LastStand [[spoiler:that ends in a StableTimeLoop as a result of EternalRecurrence]].
** Want it to be [[FromBadToWorse even more heartbreaking]]? A translation of the dialogue spoken in [[spoiler:Stage 1 "Link"]] [[https://www.youtube.com/watch?v=8qC7FfL2qzI exists online]]; not only is it poignant, but it essentially proves [[spoiler:the Stone-Like correct in its assessment of humanity]].
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