Arc Fatigue: Some chapters go on so long, and change perspective so frequently, and have so many hiatuses in-between that you completely forget what happened immediately before, during, or after the scene we're watching. Given that other characters have commented on this in story, however, it can justified as Alex's way of telling long stories.
Broken Base: The strips suggesting that Lucca saving her mother from being crippled was a bad thing did not get good reactions from some. Although it's intentional, the Sovereign of Sorrow using her powers to twist reality in a plausible but depressing direction, this wouldn't be meaningfully explained for years thanks to the comic's slow update schedule and meandering story structure.
Continuity Lock-Out: It's a fairly complex plot that touches on many, many video games and a decades-old TV show, so it easily causes this.
Crack Pairing: Dr. Wily is apparently dating Carmen Sandiego.
Now Act II has been retconned to have ended in 2004. Before the above comic was posted. Act III just ended, officially... despite the Final Fantasy VI cast, who started the whole 'Act III' gag, not having appeared yet.
The Body of the Sovereign has been mentioned to rest on a moon from FFIV. Sounds like a place a godlike being could be.
Subverted as well, also thanks to The After Years. Palom's would-be Love Interest was named Suzy in Captain SNES, and then The After Years named her Leonora.
Narm: King Hippo's flashback of the N-Team's final battle with Mother Brain (and the events that led to it) mimics the writing style of the Captain N show. The editors of the comic were none-too-pleased.
Duke's scream of agony after Mother Brain drops him into the Omega Warp, killing him off permanently. King Hippo is left a traumatized, broken husk of a man Drowning His Sorrows, even though he never cared about the victim, just because he'd never seen anyone die before.
Tear Jerker: #719, in which the N-Team and N-Forcers watch the world of Crystalis be destroyed while the main characters of that world, realizing their fate, share one final embrace.
it was joked that Chapter 2 would end in 2008... 2009, tops. Thanks to the comic's infamous Schedule Slip, that's exactly when it ended.