Dr. Mephesto hadn't been seen since "Cartman Joins NAMBLA" until the Season 14 episode, "201". In "201", the appearance of the ranch is heavily revised, and also boarded up with a large door with a peephole and multiple locks. It is revealed that Dr. Mephesto, likely due to the failure of his experiments, has become a recluse, trying to be "left alone". He refuses to allow a black man (Mitch Conner in disguise) in after a car crash (although he does give directions to a gas station) until he is accused of racism.
It is unknown if Terrance Mephesto lives with his father there, as he is not present in many of the ranch's appearances. It is possible his mother has custody.
Kyle wants to genetically engineer a pot-bellied elephant; a mix between elephant and a pot-bellied pig; by using Kyle's Elephant and Cartman's pig, Fluffy. Kyle goes to the South Park Genetic Engineering Ranch to make a pot-bellied elephant but sadly, figures out pig and elephant genes just won't splice. Dr. Mephesto takes a sample of Stan's blood to help Terrance, his son, make a human clone.
Dr. Mephesto brings Chef into the ranch to show him the turkey DNA he used to make turkeys that went horribly wrong, claiming he knew only Chef would believe him.
The people of South Park are seen at the ranch in the recap of the last episode and when Terrance and Phillip are watching American television.
Dr. Mephesto is shot at the ranch and is taken to the hospital. At the end of the episode Dr. Mephesto announces that Liane Cartman is actually a hermaphrodite which means she is Cartman's father. This is of course a cover up for the Denver Broncos as revealed in the episode "201".
Dr. Mephesto used the ranch to hold Larry.
Dr. Mephesto's ranch is used as the place where Hope (Junjun) gives birth.
Stan goes to the ranch and asks Dr. Mephesto for hormones so he can get his "period".
Cartman goes to the ranch and asks Dr. Mephesto to make him a mature friend, Dr. Mephesto says it's not that simple but if he wants to he could join NAMBLA (North American Marlon Brando Look Alikes) which Cartman mistakes for the other NAMBLA (North American Man Boy Love Association).
Cartman goes to the ranch and asks Dr. Mephesto to tell him who his real biological father is and Stan, Kyle and Kenny want him to clone Mohammed.
- "An Elephant Makes Love to a Pig" - The Boys try to genetically splice the DNA of Kyle's Elephant and Fluffy. Terrance Mephesto tries to make a human clone here.
- "Starvin' Marvin" - Mephesto tells Chef about the rabid turkeys.
- "Cartman's Mom is a Dirty Slut" - Mephesto finds the identity of Cartman's father.
- "Terrance and Phillip in Not Without My Anus" - Briefly seen in the previously segment.
- "Cartman's Mom is Still a Dirty Slut" - Mephesto is shot before he can reveal who Cartman's father is.
- "Prehistoric Ice Man" - Mephesto examines Larry.
- "Jakovasaurs" - Mephesto helps Jakov to impregnate Hope.
- "Are You There God? It's Me, Jesus" - Stan visits to get help about getting periods.
- "Cartman Joins NAMBLA" - Cartman comes to ask Mephesto to make him some mature friends, and is directed to NAMBLA.
- "201" - Cartman comes to find the truth about his father, and Stan and Kyle come to clone Muhammad.
After the Freedom Pals manage to interrogate the Coon over the location of The New Kid's parents, he tells them about an detail of Mitch Conner's plan involving the genetic engineering ranch. The team then head there, only to find they can't get in till the night. Morgan Freeman contacts the New Kid to tell them their powers to change day into night, which they use, allowing the team to get in.
Dr. Alphonse Mephesto gives the team a tour around the lab, but due to many faults they end up fighting groups of many-assed cats and sixth graders. They then find the Coon and Mitch Conner, the latter of which explains his big plan to take over South Park, which Human Kite prompts the New Kid to take a picture of.
The New Kid is sent to call the tour train and get the team out. Partway there, the New Kid finds their parents trapped, with the only way of rescuing being to either cut off their mom's arm or their dad's head and feed it into the DNA machine. With no other option, the New Kid chooses a parent and decapitates them.
When the tour train comes down with the group in, they come against Mitch Conner, who releases his genetically altered superhero, mutant Human Kite 2. The team are then forced to fight it, but find it's too strong. Mephesto prompts the New Kid to use their farts to change time to day, so the Human Kite 2 has to apply sunscreen, and the team can easily attack him. Once the mutant has finished, he continues to fight them. The New Kid continues to do this 3 or 4 times, before they are prompted to do one massive timefart, knocking the mutant unconscious.
- Dr. Mephesto - Can be selfied in the lab after The Many Asses of Dr. Mephesto is completed.
- Claw Scars - Obtained after defeating the genetically altered cats.
- Optic Penetrator - Found in a bag outside the laboratory.
- Memberberry - Found in the front yard after completing the quest.