In 2004, producer John Holmes and Seven script executive Bevan Lee decided to overhaul the show after feeling the Ward 17 storylines had become repetitive, joking about the recurring 'Hi, I'm Von, I'm your nurse' scenario after six years.

Producers considered either cancelling All Saints or using it as the basis for a spin-off before deciding instead to close Ward 17 and relocate the series' focus to the Emergency Department.

Former Always Greener star John Howard signed a three-year deal to join the cast as the gruff head of emergency, Dr. Frank Campion, when the show shifted focus in 2004.

In season eight, original lead character Terri Sullivan (Georgie Parker) was written out halfway through the year, leaving Von Ryan (Judith McGrath) as the last original cast member and prompting John Howard to move into top billing.

In 2009, the show was rebranded All Saints: Medical Response Unit (MRU) after introducing a helicopter rescue unit, a move intended to boost ratings but which reportedly inflated each episode's cost to around $500,000.

Episode 265 (2004), which introduced Frank Campion and the emergency department setting, caused controversy after his character swore at Terri Sullivan on air, prompting over 100 complaint calls in Melbourne alone; Seven did not issue an apology, citing its M classification.

Episode 432 (2008) sparked controversy after depicting a storyline suggesting incestuous relationships increase the risk of Down syndrome in offspring, a claim a leading geneticist called false; Down Syndrome Australia threatened legal action and a boycott, leading Seven to issue an on-air apology.

The first opening theme song's saxophone melody bore a striking resemblance to 'Fly by Night', the opening track of Jethro Tull frontman Ian Anderson's 1983 solo album Walk into Light.

The series finale ended with a montage of memorable moments from the show's 12-year run set to The Beatles' song 'In My Life'.