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.
Handwriting samples from Holmes and Jack the Ripper's "From Hell" letter at least 97% matched. The reason these murders are attributed to Holmes is due to at least a few of them being killed by mutilation of their organs. It is thought only a surgically trained doctor could pull this off. Mysteriously, these murders took place during a blind spot in Holmes's recorded history. This has led many, including some of Holmes's descendants, to believe That H. H. Holmes is, indeed, Jack the Ripper. If this is true, Elizabeth Stride would have been another victim of his.
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.