The series follows U.S. Secret Service Agents Myka Bering (Joanne Kelly) and Pete Lattimer (Eddie McClintock) when they are assigned to the government's secret Warehouse 13 for supernatural artifacts. It is located in a barren landscape in South Dakota, and they initially regard the assignment as punishment. As they go about their assignments to retrieve missing artifacts and investigate reports of new ones, they come to understand the importance of what they are doing.
In Season 1, Episode 5, they meet Claudia Donovan (Allison Scagliotti), who is searching for her missing brother; in Season 2, she joins the team as their techno-wiz. In Season 3, Episode 1, Steve Jinks (Aaron Ashmore), an Agent from Bureau of Alcohol, Tobacco, Firearms and Explosives (ATF) comes aboard.