With acting boss Jackie Aprile dying of cancer, Tony prepares for a power struggle with Uncle Junior. Christopher and his associate Brendan make trouble for themselves when they jack a truck full of DVD players. Tony's mother Livia finally agrees to live in a retirement community. Big Pussy and Paulie Walnuts are sent to find a stolen car.

Uncle Junior's associate Mikey Palmice stirs things up by making Junior think Tony wants to be next in line for boss. Meanwhile, Tony, Paulie and Silvio deal with Hasidic family problems.

Jackie Aprile's health worsens, forcing Tony to make a tough decision. Meanwhile, Anthony Jr. learns the true nature of his father's job in 'waste management.' Also, Tony hires sleazy police lieutenant Vin Makazian to investigate Dr. Melfi's background.

At Tony's suggestion, Junior is made acting boss after Jackie dies. In therapy, Tony surprises Dr. Melfi with an admission. Carmela and Irina (Tony's mistress) both suffer as Tony's libido takes a nosedive.

At the wedding of Larry Boy's daughter, the 'boys' find out they're going to be indicted, and make a premature exit to get rid of incriminating evidence at home. Upset that he isn't getting the notoriety of other family members, an agitated Christopher has an ugly encounter with a bakery clerk.

Uncle Junior enjoys a romantic tryst in Boca with his girlfriend Bobbi, not realizing that she's been gabbing to her beauty-parlor friends about his oral talents. Meanwhile, controversy arises when Meadow's soccer coach announces he's leaving the school.

After Jimmy and Pussy are arrested in an FBI raid, Makazian tells a stunned Tony that Pussy may be wired for the Feds. Tony sends Paulie to find out for sure. Later, Tony learns that Makazian might be trying to frame Pussy to get out of his gambling debts.

Hit men are sent out to whack Tony, who comes out of his depression when he meets Isabella, an Italian exchange student staying next door.

In the Season One finale, Tony is stunned to discover that the attempt on his life may have been ordered by someone very close to him. Later, he must deal with the fact that everyone knows he is seeing a shrink. Christopher is sent to take care of Jimmy Altieri.

Tony escapes to the Plaza Hotel for a night of rest and relaxation, but his dreams are haunted by past faces. Another casualty falls in the war between Johnny Sack and Little Carmine, and Tony B. heads to New York for revenge.