[17] Two weeks after finishing her run in Blood Brothers, Lancashire auditioned for the role of new Coronation Street character Raquel Wolstenhulme, a colleague of supermarket employee Norman "Curly" Watts (Kevin Kennedy).

[32] In February 1999 she made a guest appearance in the British dark comedy anthology series Murder Most Horrid alongside comedian Dawn French.

[35] The series' producer at the time, Jane Macnaught, deemed Raquel one of Coronation Street's most popular ever characters and her return an opportunity for her "millions of fans" to learn what had become of her.

[36] From late January, Lancashire appeared as factory employee Yvonne Kolakowski, a widow with a dysfunctional personal life, in the BBC One drama series Clocking Off.

[37] Lancashire found shooting the drama, which detailed Atkins' decision to quit her acting career in order to set up a care home for abused children, "mentally draining".

[42] Resulting from Lancashire's ability to connect with a television audience, ITV sought to secure her exclusively to their network in a two-year golden handcuffs deal, which was finalised in July 2000.

[45][46] Discussing the exclusive signing ITV controller of drama Nick Elliott identified Lancashire as being someone with "a great range [who] creates a tremendous empathy with an audience".

[43][44] The television film, which aired on New Year's Day 2001, was Lancashire's first in the costume drama genre; she played a housekeeper harbouring romantic feelings for her employer (Billy Connolly).

[43][50][51] In October Lancashire starred in an adaptation of the Michelle Magorian novel Back Home as Peggy Dickinson, a woman adjusting to life in post-war Britain after having been separated from her family during the war.

[62] On 22 December she appeared in the television movie Birthday Girl as Rachel Jones, who plans a party to celebrate being in remission from a serious illness, only to discover that the disease has returned.

The portrayal –her first of a mother with adult children– followed Gertrude's transformation from a young bride into a fifty-something woman ravaged by her life experiences of poverty and domestic abuse.

[19] Reviewing the serial, Paul Hoggart of The Times wrote that Lancashire "steals the show" with a "performance of immense subtlety and quiet strength, proof, if we still needed it, that she has matured into a terrific actress.

[79] In November, she presented an episode of the Five documentary series Disappearing Britain in which she interviewed people with memories of Wakes Week holidays in Blackpool during the early 20th century.

[85] Whilst ambivalent about the serial as a whole, The Daily Mirror's Jane Simon singled Lancashire out for praise stating that she "really sets the tone for the cold, unfeeling world into which orphaned Oliver is born.

"[86] Between 2008 and 2011, Lancashire narrated the BBC One series Lark Rise to Candleford, a costume drama based on Flora Thompson's memoir of her Oxfordshire childhood in the 1880s.

[91] Following this, she reunited with director Coky Giedroyc, who had directed her in Oliver Twist, for a 2009 television adaptation of Emily Brontë's 1847 novel Wuthering Heights in which she played housekeeper Nelly Dean.

[97] In the production, a loose adaptation of the 1984 film A Private Function, she starred as Joyce Chilvers, an aspirational housewife who Lancashire describes as "brittle" and "capricious".

[102] In September 2012, Lancashire began appearing as Head of Ladieswear Miss Audrey in the six-part series The Paradise set in a department store in Northern England in the late 19th century.

[103][104] Lancashire described her character as "a true archetypal spinster" who has long denied herself a romantic life and who begins to feel undermined by a younger colleague.

[104] Between November 2012 and March 2020, Lancashire appeared opposite Anne Reid and Derek Jacobi in the BBC drama series Last Tango in Halifax.

[105] Caroline's same-sex relationship with a fellow teacher resulted in Lancashire receiving more fan mail than for any other role,[4] largely from women telling her that the series had helped them to come out.

[113] Lancashire portrays single-grandparent Catherine Cawood, a police sergeant still dealing with the aftermath of her daughter's rape, and subsequent suicide, eight years earlier.

[4][113] Mark Lawson of The Guardian identified the performance as a career best for Lancashire, stating that she perfectly conveyed "the script's demandingly contradictory notes of tragedy, comedy, love, guilt, weakness and courage".

[119] Despite Lancashire's concerns regarding the decision to extend the story told in Happy Valley, Wainwright's "genuine" storytelling and "integrity" convinced her to return for a second series, which aired in 2016.

[124] In the drama, which aired in October 2015, Lancashire portrayed stage manager Madge, whose unrequited love for 'Sir' (Anthony Hopkins), the head of a repertory theatre company, puts her at odds with his dresser and confidant, Norman (Ian McKellen).

[128] Lancashire was due to appear opposite Martin Freeman in Labour of Love, a political comedy by James Graham, at the Noël Coward Theatre in late 2017[129] but pulled out on 1 September "on doctor's advice" and was replaced by Tamsin Greig.

[130] In 2018, she starred as Miriam – billed as an "experienced, no-nonsense social worker" – in Kiri, a four-part drama series written by Jack Thorne, co-produced by Channel 4 and the American on-demand service Hulu.

[131] The miniseries centres on a black girl living with a white foster couple who is murdered on a visit to her family, putting Miriam and the social services under scrutiny.

[134] Other steps that Lancashire took to combat her depression included remaining single for five years, attending therapy sessions and taking the anti-depressant drug Paroxetine.

[134] The two had begun a romantic relationship in the summer of 2000,[134] though they had first met several years earlier while she was portraying Raquel on Coronation Street and he was employed by Granada Studios, which produces the soap opera.