A spy known only as Mr. Smith (Scott Bakula) works for a private security organization known as "The Factory". Using covert operatives and the latest technology they gather information on technology, science, and economics in an effort to protect corporate America from espionage. They are also hired out as private security or to help with covert operations like the recovery of stolen Stinger missiles. In the pilot, a rival named Mrs. Smith (Maria Bello) becomes entangled on a case with Mr. Smith. After losing her job when her mission fails, The Factory hires her and assigns them to work together. Though they often bicker, and know nothing about each other's personal lives, including real names, they make a good team.
Now forced to work together and masquerading as a suburban couple, ""Mr. and Mrs. Smith"" spy on their neighbor who is suspected of stealing top-secret information from his employer.
Mr. and Mrs. Smith go to Italy's Napa Valley to find out who is trying to use genetically engineered insects to destroy the grape crop, and Mr. Smith learns more about his mysterious partner's past.
While searching for two missing physicists who've made a breakthrough in cold fusion, a secret agent encounters an equally secret and capable blonde who is in competition with him.
Mr. and Mrs. Smith go after the scientist son of a former astronaut, who has sold his novel flying platform to crooked military contractor who wants to turn it into a weapon.
Mr. & Mrs. Jones are sent in to retrieve stolen currency plates from the treasury department. When Mrs. Jones gets shot Mr. & Mrs. Smith gets called in to finish the job.
The Smiths poses as ""Spin Doctors"" for a New Orleans senator who's involved in a scandal where his girlfriend is accused of selling defense secrets to Iraq. Together with Rox they are trying to expose the real culprit.
The Smiths and a CIA-agent lose a ball of Plutonium-239 due to the interference of Bob Myers, an old friend of Jerry Rawlins (Mr. Smith). Now they must retrieve the Plutonium and protect Bob from the terrorist.
Mr. Smith disappears during a mission and leaves Mrs. Smith hanging. She escapes and begins to search for the missing Mr. Smith. Meanwhile, he finds out that his son has been kidnapped and to get him back he must kill a man.