"All my stories, unconnected as they may be, are based on the fundamental lore or legend that this world was inhabited at one time by another race who, in practising black magic, lost their foothold and were expelled, yet live on outside ever ready to take possession of this earth again.” - Harold Farnese, misquoting H.P. Lovecraft

The essence of the Mythos is that the entirety of humanity is insignificant on a cosmic scale. The human world is but a fragile bubble in an infinitely vast and indifferent universe, isolated by great gulfs of both time and space. Though we consider ourselves masters of all creation, as a species our limited perceptions allow us to see only a fraction of the full range of reality. Beyond our pathetic awareness dwell vast and ancient forces, completely beyond our ability to influence in any way, whose merest thoughtless twitch would annihilate every trace of humanity. Our seeming dominance over the world is illusory and ephemeral. We are blessed in that we do not realize what lies dormant and unknown in forgotten places on Earth and beyond. As Lovecraft famously begins his short story, The Call of Cthulhu, "The most merciful thing in the world, I think, is the inability of the human mind to correlate all its contents."

Now and then, individuals can, by accident or Carelessness, catch a glimpse of, or even confront the ancient extraterrestrial entities that the mythology centers on, usually with fatal consequences. Other times, they are represented by their non-human worshipers, whose existence shatters the worldview of those who stumble across them. Human followers exist as well. Because of the limitations of the human mind, these deities appear as so overwhelming that they can often drive a person insane. They are portrayed as neither good nor evil. Within the Mythos these are concepts invented by our species as a way to explain intentions and actions which may otherwise seem inexplicable.

The Call of Cthulhu was the premiere story in which Lovecraft realized and made full use of these themes, which is why his mythology would later be named after the creature in this story, as it defined a new direction in both his authorship and in the horror fiction genre. This is also the only story by Lovecraft where humans and one of the cosmic entities called the Great Old Ones come face to face.

In his final years, Lovecraft used fewer supernatural elements to represent the dangers which threaten humanity. Instead, he gradually replaced them with non-supernatural cosmic beings and phenomena, based on principles outside the laws of nature in our own space-time continuum. This science-fictional trend particularly becomes clear in works such as At the Mountains of Madness. Many of these later tales also humanize these aliens to some extent, and the degree to which they still retain the theme of nihilistic horror varies.