Unlike most of the demons, spirits, and creatures that the Winchester brothers hunt, the ghost in this episode is based on a real-life historical figure: the serial killer Herman Webster Mudgett (1861-1896), a.k.a. Dr. Henry Howard Holmes. Many of the details mentioned by the Winchesters about H. H. Holmes are historically true: he did confess to 27 murders (9 confirmed); he did build a so-called "Murder Castle" in Chicago so he would be able to carry out his crimes in secret; there is evidence that he used chloroform in at least some of his crimes; he was executed by hanging in Philadelphia; and, at his request, he was buried in concrete so no one would be able to molest his corpse.
The photograph of the victim H.H. Holmes was said to have murdered was actually a photograph of Jack the Ripper's victim - Elizabeth Stride, 1888.
Jared Padalecki is noticeably absent from most of the action in this episode. His schedule was cleared to allow him more time to fully recover from a broken hand injury that he incurred a few episodes back.
Dean mentions a girl in L.A. kidnapped by an evil cult, a girl named Katie Holmes. This episode aired about a year after Katie Holmes started dating Tom Cruise, who is infamously involved with Scientology.
When they find ectoplasm in the wall socket, Dean says, "Well, Sam, I think I know what we're dealing with here. It's the Stay-Puft Marshmallow Man." The Stay-Puff Marshmallow Man is the 10-story tall gooey earthly embodiment of Gozer the Destructor as envisioned by Ray Stantz in Ghostbusters (1984).