Walter Hartwell White (also known by his clandestine alias Heisenberg) (played by Bryan Cranston) is an underachieving Albuquerque, New Mexico high school chemistry teacher who, after being diagnosed with lung cancer, starts manufacturing methamphetamine to provide for his family upon his death. Knowing nothing about the drug trade, he enlists the aid of his former student, Jesse Pinkman, to sell the meth he produces. Walt's scientific knowledge and dedication to quality lead him to produce crystal meth that is purer and more potent than any competitors'.

Jesse Bruce Pinkman (played by Aaron Paul) is a small-time methamphetamine user, manufacturer, and dealer. In high school, he was an indifferent student in Walter White's chemistry class. Now in his mid-20s, Jesse is Walt's business partner in the meth trade. Jesse is impulsive, hedonistic, and uneducated beyond high school, but he is financially ambitious and streetwise. He talks in playful slang, likes to wear garish clothing that follows the latest trends in youth culture, plays video games, listens to rap and rock music, takes recreational drugs, and drives cars outfitted with gadgets to make them "bounce."

Skyler White (née Lambert) (played by Anna Gunn) is Walter's wife. She has had several meager sources of income: writing short stories, selling items on eBay, working as a bookkeeper, and ultimately helping her husband launder money. Skyler and Walter have a son, Walter Jr., and an infant daughter, Holly. Skyler cares for Walter very much, but their marriage becomes increasingly strained due to his unexplained absences and bizarre behavior, ultimately leading to their separation. Later, once Walter reveals his operation, she aids him in laundering his funds.

Henry R. "Hank" Schrader (played by Dean Norris) is Walt and Skyler's brother-in-law and Marie's husband, who works as a U.S. Drug Enforcement Administration agent. He is involved in investigating a meth dealer known as "Heisenberg," unaware for over a year that his prey is actually Walter. Hank has a cavalier exterior, but in reality the dark side of his job affects him more than he cares to admit.

Saul Goodman (played by Bob Odenkirk), real name James Morgan McGill, is a sleazy "criminal lawyer" (in Jesse Pinkman's words: "a lawyer who is a criminal") who acts as Walter and Jesse's attorney and up to a certain point, the series' comic relief. He uses the name "Saul Goodman" because he thinks his clients feel more confident with a Jewish lawyer; this name is also homophonous with the expression "[it]'s all good, man". Dressing in flashy suits, Saul maintains extensive connections within the criminal underworld and serves as a go-between connecting drug distributors, evidence removers, impersonators, and other criminals-for-hire.