66 Seals

The 66 Seals are intangible "locks" manufactured by God to secure Lucifer's Cage, rather are actually events/situations. Much of Season 4 revolves around the Winchesters attempting (unsuccessfully) to stop the demons from breaking the seals.

Background
After Lucifer fell from grace and rebelled, God bound him into his cage deep in the pits of Hell and locked the cage with 66 Seals, which needed to be broken by any demon or angel wishing to free the Devil. As described by Castiel, the Seals are equivalent to locks on a door, and breaking them all opens the door. The Seals are metaphors, as they are events which need to occur in order to release Lucifer.

Lilith, the first demon, was released by Azazel under Lucifer's orders, as she was described to have the capability to break the seals. In addition, Lilith herself was the last seal that can open the cage.

With the first seal broken, the angels head down to Earth in an attempt to stop the ascent of Lucifer, but they were foiled by the combined efforts of Lilith, Ruby, and Sam Winchester. Even though only 66 need to be broken, Anna Milton mentioned that there were over 600 possible seals - making it difficult for the angels to predict which one will be broken next. In "Lucifer Rising", Sam Winchester broke the final seal when he killed Lilith, thus setting Lucifer free. In the same episode, it is revealed that the "Senior Management" of Heaven deliberately allowed the 66 Seals to be broken so that Lucifer could be freed and then killed by Michael.

Appearances and mentions

 * When Dean Winchester was in Hell and gave in to Alastair's torture and started torturing souls himself, he broke the first Seal by being the first righteous man to shed blood in Hell. (On The Head Of A Pin)
 * The "Rising of the Witnesses", was another Seal broken by Lilith in "Are You There God? It's Me, Dean Winchester".
 * When Samhain rose on Halloween, this broke a third Seal ("It's the Great Pumpkin, Sam Winchester").
 * In "Criss Angel Is a Douchebag", Ruby mentions that Lilith has broken 34 Seals of the 66 so far.
 * In "Death Takes a Holiday", Alastair attempts to kill two Reapers on a Solstice to break another Seal. He killed one, but the Winchesters stopped him before he could kill the other Reaper, Tessa.
 * In The Monster at the End of This Book Lilith offers to stop breaking Seals in exchange for Sam and Dean's deaths.
 * Ten species go extinct in Key West, breaking another Seal. ("When the Levee Breaks")
 * Fifteen fishermen go blind on a fishing trip in Alaska, breaking another Seal. ("When the Levee Breaks")
 * A teacher in a New York school locks the doors of the classroom and kills sixty-six school children, breaking another Seal. ("When the Levee Breaks")
 * "And it is written, that the first demon shall be the last Seal". This occurs in "Lucifer Rising" when Sam kills Lilith with Ruby's encouragement, enabling Lucifer to burst out of his Cage and walk the Earth.

Note

 * There are supposedly at least 534 Seals currently remaining. It is unknown if breaking another 66 can re-open the Cage. This is however unlikely, given that Lilith (the first demon and the last seal) is dead, and that the only Special Child alive is Sam.