Set in the near future in the Great Era of Detectives, chosen people are born with supernatural abilities known as Toys (トイズ, Toizu). Those who use these Toys for evil are responsible for a wave of crimes and necessitate employing Toy-using detectives to help solve them. In the Yokohama District, Opera Kobayashi runs a detective agency named Milky Holmes, made up of four budding young detectives, Sherlock Shellingford, Nero Yuzurizaki, Hercule Barton and Cordelia Glauca, who each wield their own unique toys and train to become detectives at Holmes Detective Academy.

The video game casts players in the role of Kobayashi, who must utilise Milky Holmes' unique abilities to stop the Thieves' Empire, a band of thieves led by the mysterious Arséne. The second puts players in the role of another detective, Ellery Himeyuri. The Alternative TV specials also take place in this universe, in which Kobayashi and Milky Holmes are assisted by another Toy user, Lily Adler, in fighting against the Thieves' Empire whilst visiting London.

In the first two television anime series, the four girls of Milky Holmes, Sherlock, Nero, Hercule and Cordelia, end up losing their Toys during an encounter with the Thieves' Empire. Taken away from their rich lifestyle and thrown into an attic, the girls must try and regain use of their Toys or else face expulsion from Holmes Detective Academy.

Futari wa Milky Holmes, which takes place two years after the other series, follows two young girls, Alice and Kazumi, who, inspired by Milky Holmes, form their own detective unit, Feathers, and fight against a group of thieves known as the Color the Phantom.

Tantei Opera Milky Holmes (探偵オペラ ミルキィホームズ, Tantei Opera Mirukii Hōmuzu, lit. "Detective Opera Milky Holmes") is a media franchise owned by the Japanese trading card game company Bushiroad. The first release was an Internet radio drama, released in December 2009. An anime adaptation by J.C.Staff aired between October and December 2010, with a special episode aired on August 26, 2011. The second anime season aired between January and March 2012 with another special aired on August 25, 2012. A third series, titled Futari wa Milky Holmes, aired between July and September 2013.^[3] A fourth series titled Tantei Kageki Milky Holmes TD is scheduled to air from January 2015. Other media includes a manga adaptation serialized in Comp Ace between May 2010 and January 2011; two visual novels, released for the PlayStation Portable in December 2010 and August 2012 respectively; a trading card game tie-in with Bushiroad's Weiß Schwarz; and a light novel series published by ASCII Media Works under their Dengeki Bunko label.

The series is a homage to the detective fiction genre, with the four female leads named after famous fictional detectives: Sherlock Holmes, Nero Wolfe, Hercule Poirot and Cordelia Gray. Milky Holmes is also the name of a voice acting unit consisting of the series' four main voice actresses; Suzuko Mimori, Sora Tokui, Mikoi Sasaki and Izumi Kitta.