Lisa is the second of three kids to Homer and Marge Simpson, she is the younger sister to Bart, and older sister to Maggie. Not long after Marge had discovered that she was pregnant for the second time, she and Homer agreed that it was about time that they moved into a bigger house which did not sit well with Bart. When she was born, Bart was extremely jealous of his new sister. He cut her hair, pushed her into a mailbox and through Flanders's Doggie door (despite him never having a dog). As Bart is about to run away from home, Lisa toddles into his room and utters her first word, which is his name and the two form a close bond. That is until the two get older when traditional sibling rivalry kicks in, though the two fight often, the pair do care about each other, and Bart will always come to Lisa's aid when she needs it as much as she goes to Bart's aid when he needs it also.

Lisa is quite the genius. She is a member of MENSA with an IQ of 159, Lisa often uses these smarts to assist or torment her brother. She is the brains of the operation when it comes to solving mysteries such as reuniting Krusty with his father or foiling another one of Sideshow Bob's schemes. When Lisa was three she managed to solve a jig-saw puzzle easily, is able to write words with her blocks, and can create a horse out of clay. To nurture these talents, Homer buys Lisa her first Saxaphone, when that one is destroyed, he buys another for which she plays Baker Street on.

Lisa is very pasionate about the environment, and will go at any length to help protect it. She once lived in a tree for several days before missing home and it was torn down by lightning, she has staged numerous protests around Springfield, and has become a Vegetarian with the help of Apu, and Paul and Linda McCartney. Lisa is also a member of PETA though, Marge thinks that she simply awnsers their phone, and she was also a member of Dirt First.

Lisa has proven herself to have wide range of talents besides the sax. She can play the guitar quite well, along with various other intruments, she's quite an actress, and is exceptionally good at Ice Hockey in the goalkeeper possition.

Despite her grown-up persona, she is still a kid at heart and particularly enjoys Itchy and Scratchy and idots Krusty the Clown (though not as much as she does the Late Bleeding Gums Murphy), she also loves ponies and even had one of her own in 8F06 - Lisa's Pony and she also loves the idea of unicorns, even when she knows they are fake.

Like Bart, one of Lisa's main enemies is Sideshow Bob still out for revenge for putting him in jail for framing Krusty. Lisa is usually more forgiving to Sideshow Bob's fake reform schemes than Bart is as Bart never stops believing that Bob is up to something, and his assumptions are usually correct. Lisa also has a few rivals, namely Allison Taylor, who was younger, smarter and had a better lung capacity. Lisa requested Bart's help to make her look bad, but guilt overcame Lisa and the two became friends instead.

Lisa has had a number of boyfriends and crushes. The first is Nelson Muntz who she gained a crush on after he was tormenting Groundskeeper Willie, she tried to change him into a better person, but failed. She decided to stop dating for a while after that. Other crushes include Jesse Grass, which resulted in her joining Dirt First, Thelonius, a student from West Springfield Elementary, and Luke Stetson a junior wrangler at the Lazy Eye Ranch. Most recently, she has started to date Colin, in The Simpsons Movie. Just like she gets some have crushed on her, the first, Ralph Wiggum developed a crush on her when she gave him a valentine card in 9F13 - I Love Lisa, and Milhouse Van Houten who has had a crush on her since kindergarten, and he's always trying to hit on her, but she likes to refer to him as a big sister.