Sasha visits her sister and her new puppies in Los Angeles, leaving Charlie and Itchy in charge of the Flea Bite until she returns.

For having messed up three missions in a row, Charlie's put on probation by Annabelle so isn't allowed to do, say, or even think anything bad until he does a good deed. When Carface and Killer take over the Flea Bite Café and turn it into an arcade, Charlie and Itchy have to cross-dress to get the café back.

While traipsing in a snooty Nob Hill area, Charlie and Itchy are lured into a trap set by a bratty dog-hating kid named Teddy.

Carface gets his hands on a dangerous substance able to turn dogs into monsters. He and Killer taint Charlie's dog food, and Charlie turns into a monster. Carface and Killer plan to use Charlie to steal for them, and then turn Charlie in. Itchy learns about this situation and goes to rescue his best friend.

Charlie falls into a coma and has a dream of becoming a 1930s era detective to find out about a cat-scheme.

Itchy gets sent to the pound and has to break out with help from Killer.

Bess is being threatened by her ex Manfred and wants out to be with Itchy. Itchy tries everything to protect her but it's Charlie who saves Bess. Itchy is later hypnotized by a magician who turns him into a superhero.

A magic multiplying box spells three times the trouble when Charlie overbooks his afternoon between a date with Sasha, his poker buddies, and a fight with Otto and his gang.

Charlie needs a vacation, and manages to convince Itchy into taking one, but with so many bad things happening, Charlie can't even go a block without being someone's Guardian Angel.

Charlie and Itchy are sent on a seemingly nefarious mission, unaware that who they believe is Annabelle is in fact her demonic cousin Belladonna.

Itchy is unable to properly beg for food, unlike Charlie, who masters it quite often. Under Charlie's guidance, Itchy begs a spoiled rich girl for ice cream, who, in return, takes Itchy as a new pet. Meanwhile, Carface and Killer have picked the same house as their next target in a string of burglaries.

Itchy gets so scared that he can't help Charlie, who decides it's time for Itchy to face his fears. He tells Itchy that they are spending the night in a supposedly haunted mansion, unaware that it's not just superstition.

Anabelle assigns Charlie and Itchy to find a home for a little puppy. The puppy turns out to be extremely wild and impossible to find a home. Charlie, however, discovers that Sasha is impressed with his nobility he is when caring for the pup.

It's David's 10th birthday and he's received a voice recorder. However, it gets him study hall from the vice principal, so Charlie and Itchy bust him out for a day of fun but must watch the clock to get their human friend back in time.

Bess and Sasha plan a double date with Charlie and Itchy, unaware that the bickering buddies have had their personality souls swapped by Annabelle.

Charlie auditions to be the new spokes-dog for Gulpo Dog Food, but the company picks Itchy instead. Now Itchy's famous and Charlie's left sulking in the Flea Bite Café, leaving everyone wondering, 'Will success spoil Itchy Itchiford?'

Annabelle assigns the duo on a mission to help a boy named Leon join his Little League team. What Charlie doesn't know is that this is Itchy's twentieth mission, and if successful, he will be reallowed entry to Heaven. With the separation between him and his best friend at stake, Charlie struggles with moral dilemma: to deliberately tank the mission or help out and let Itchy go back to Heaven.

Charlie volunteers to go get notes that David's crush Alex left in her mom's car, but Sasha must go with Charlie instead. Charlie, however, doesn't see women as good partners for this type of thing. Sasha decides to show Charlie what women can do.

Itchy is frightened by a wilderness movie, but Charlie tells Itchy that every dog has wolf blood in them, even Itchy. And so Charlie decides that they are going on a trip into the wild, so Itchy can live up to his heritage. They encounter a lost girl scout named Charlotte, and help her find her troop.

Assigned to guard a crystal, Charlie and Itchy continue goofing off, but Charlie becomes convinced he's seen a UFO and Itchy doesn't believe him. The 'aliens', actually Carface and Killer, break into Charlie and Itchy's home and steal the crystal, prompting Charlie to get it back.

Charlie has been lying a bit too much lately, so Anabelle makes his nose grow every time he tells a lie. Charlie must start telling the truth or face the consequences.

Circus animals are being mistreated, and Charlie and Itchy are on the case. They learn that an elephant named Nelly is abused, and it's their job to videotape it and send it to Animal Control.