Foglets are evolutionary dead-ends.Think about it. They may be practically immortal, have the ability to assemble just about anything out of literally thin air, and likely possess quite a few other incredible abilities. However they're not omniscient, don't seem to have any ability to reproduce themselves, and it is implied that they are unable to leave the City. Most important is that "going foglet" is a one-way process, which would also imply that once you go foglet, you can't change into anything else or make any modifications to the foglet form. It also adds rationale to the existence of the Farsight Reservation, which tries to do things more differently specifically because foglets are dead-ends.
The setting of the story is Twenty Minutes into the Future.Telling the "Revivals" the length of time that they've been frozen causes them to Go Mad from the Revelation not because it's so long, but because the world has changed so much in at most a few decades.
The Singularity has happenedIt's just that they were so disgusted with humanity they left the known universe. Whether they left or not is unknown, but Spider does mention transhumans in passing.
Spider's cognitive dysfunctions are partially due to the effects of the I-pollen exposure, and not JUST his drug useThis probably falls into Reasonably Probable Conjecture rather Wild Mass Guessing, but I thought I'd throw out the idea and see what people have to say.
The world of Transmetropolitan takes place after Third Impact.It explains the Gladiator Wall, how uninhibited everyone is, the apocalyptic past Spider refers to, and how we got such exact mastery of the human genome.
The City is actually Gotham.Spider and the Smiler are their day's version of Batman and the Joker.
Spider is descended from Herr Starr.Spider's ancestor was the product of Starr and an enterprising French prostitute in his early days in the Grail movement. Spider's bloodline doomed him to become a bald, impulsive sadist freak with a set of idealistic beliefs to adhere to and several more to utterly destroy.