Many episodes are either named after movies ("Children Shouldn't Play with Dead Things", "The Usual Suspects", "I Know What You Did Last Summer") or classic rock songs ("In My Time of Dying", "Born Under a Bad Sign", "What is and What Should Never Be", "Sympathy For The Devil", "When The Levee Breaks").
An important aspect of the show's music is classic rock, most of which comes from creator Eric Kripke's own record collection, although one of his favorite bands - Led Zeppelin - has always been too expensive to license.
Originally Jensen Ackles auditioned for the role of Sam Winchester. When Jared Padalecki came in and read for Sam a slight recasting was done. Producers called Jensen and asked if he'd rather use his charm for Dean, saying he was the Han Solo character of the duo and what kid didn't grow up wanting to be Han Solo? Jensen accepted. It became known that he was previously interested in that role, because Dean was funny.
Early on in the series, Dean's cell number is given, and for a while the studio had it set up so that anyone dialing the number would hear Jensen Ackles reading the message: "This is Dean Winchester. If this is an emergency, leave a message. If you are calling about 11-2-83, page me with your coordinates." The number is 1-866-907-3235.
To keep their cover as fighters of the Supernatural, Sam and Dean Winchester often pose as agents from varying agencies (FBI, Homeland Security, CDC, etc). The pseudonyms they use as officials are often direct allusions to rock stars, such as agents "Angus and Young," an homage to Angus Young from AC/DC or agents "Tyler and Perry," an allusion to Steven Tyler and Joe Perry of Aerosmith. Several times in particular Dean refers to himself as "Van Halen," an allusion to any member of the famous '80s rock band. In later seasons, the Winchester brothers refer to themselves as agents "Plant and Page," an allusion to the members of "Led Zeppelin," (Eric Kripke's' favorite band) or agents "Shaw and DeYoung," an allusion to the members of "Styx," some of whose music is featured in the series.
Many of the episodes are based on existing legends, myths, and ghost stories. For example the episode "Crossroads" is based in part on the legend of Robert Johnson - who in turn borrowed it from another Blues singer.
Riverview Hospital, a large mental health facility used as the main set in the season 1 episode Asylum, has also substituted for a prison, a regular hospital, and an apartment building on different episodes of the show. This is evidenced by seeing the same distinctive staircase in different episodes.
While it maybe coincidental the choice of the name Winchester for the family is interesting. There is a rather famous mansion in California built by Sarah Winchester, wife of the gun magnate, which was under constant construction for 38 years for paranormal reasons. According to legend the reason for the constant building was a medium telling Mrs. Winchester that if she ever stopped building the spirits of those killed by Winchester rifles would come after her. The strange design of the mansion is also attributed to this. It was built with dead ends and stairs to nowhere allegedly to confuse spirits.
Dean's car, up until episode 2.20, had Kansas (the brother's origin state) plates with the number KAZ 2Y5. It currently now has Ohio (Supernatural's creator Eric Kripke's home state) plates with the number CNK 80Q3.
Both Jared Padalecki and Jensen Ackles auditioned for the role of Superman/Clark Kent in some form. Padalecki was a finalist for director McG's reboot while Ackles was the second choice to play a young Clark Kent in the show Smallville (2001). Jensen was later cast as Jason Teague in Season 4.
The trivia items below may give away important plot points.
Genevieve Cortese' was cast as the character Ruby for the fourth season (replacing Katie Cassidy), and her character eventually becomes romantically involved with Sam (Jared Padalecki). In their real lives, Cortese and Padalecki also became romantically involved, and after they married in 2010, she changed her last name to "Padalecki" both personally and professionally.
Producers considered several methods of motivating Sam to take to the road with Dean. Turning Jessica evil was an option briefly, but in taking a page from Star Wars it was decided that her death would be the ultimate motivation for leaving home.
Several references throughout his appearances on the series point toward the character Rufus Turner (played by Steven Williams) being Jewish. He makes jokes about Hanukkah and keeping kosher, and most significantly, when he dies, the Winchester brothers and Bobby give him a funeral in a Jewish cemetery and discuss his level of Jewish ritual observance (or lack thereof). Although the funerals for previous hunters had included a ceremonial funeral pyre, the show makes a point of showing that Rufus gets buried without cremation (since cremation is against Jewish tradition).