The setting is Earth in 2085 during a worldwide conflict known as the Aeon War, (from the Necronomicon quote: "And with strange aeons even death may die") wherein the planet has been invaded twice: once by a black-skinned manufactured alien race known as the Nazzadi who are derived from humans and who join forces with them, and then a second time by the Mi-Go, an advanced alien civilization seemingly bent on the enslavement of humanity.

Aside from these conflicts, the game focuses on other factions, such as ancient cults like the Esoteric Order of Dagon that are running amok across the planet and the eldritch horrors that are rising to destroy the world as, according to the prophecies of the Cthulhu Mythos, the "stars are right" and the Great Old Ones and their servitors are returning/reawakening to reclaim the Earth.

[2]: 249  CthulhuTech combines the concepts of magic, mecha and the Cthulhu Mythos, in a science-fiction game in which mankind must fight a war against alien races such as the mi-go and others.

They can also select Drawbacks, such as poverty or sickness, that will give them extra points to spend at the cost of suffering an ill effect, either as a direct penalty, or as part of the storyline.

All alien monstrosities have a fear factor that forces a Tenacity roll – should the player fail, he or she will be scared or panicked by the presence of the monster, which may have scarring effects on the character's psyche.

As well, coming into contact with aliens and demons, performing sorcery, utilizing psychic abilities, or witnessing horrible events, could lead players to gain points of Insanity.

The remainder of the civilized world has joined forces to create the New Earth Government, comprising mainly Western Europe, China, Japan, Australia, Africa, and the Americas.

Vast swathes of Asian and European territory have been destroyed by the rapidly expanding Rapine Storm, a cult of crazed psychopaths and cannibals who ravage the land in hordes of armed men and terrifying alien beasts.

The CthulhuTech companion book Vade Mecum introduced three new playable races, two of which are results of Nazzadi and Human coupling and are referred to as "Xenomixes."

The third is the monstrous "Ghoul," a race of filthy and only vaguely humanoid creatures that hide within human civilization, disguising themselves as homeless people or living in sewers and tunnels.

Factions include the "Tagers," a group of warriors who work for the mysterious Eldritch Society and bond with alien symbionts that produce alien-like suits of flesh over their bodies, giving them enhanced strength and other abilities.

Tagers combat the powerful and nearly all-encompassing Chrysalis Corporation, a front for a terrible cult known as the Children of Chaos, who worship Nyarlahotep, and create shapeshifting super soldiers called "Dhohanoids" to accomplish their ends.

NEG players will fight the cults and the alien Mi-Go using mecha and military technology out in the battlefields or sorcery, wits, and investigative ability in the futuristic urban arcologies.

A few Mythos elements have been extrapolated into a futuristic setting, such as monstrous Ghouls and Byakhee, the alien Mi-Go, as well as Lovecraftian deities such as Cthulhu and Hastur.

[3] The reviewer referred to the artwork as "amazing, really helping to evoke the gloomy, decadent world of CthulhuTech" and recommended the book for those who are looking for a dark RPG.

For those categories it won Gold ENnie awards for "Best Cover Art" (Core Rule Book) and "Best Supplement" (Vade Mecum).