[6] It was named after the (then) dean of the Faculty of Medicine at Melbourne University, Peter MacCallum who, with Rutherford Kaye-Scott, had a significant role in its founding.

It was thought that because radiotherapy was also quite commonly used at that time to treat non-cancerous conditions such as severe acne, "strawberry birthmarks", frozen shoulders, keloid scars and also to provide a valuable and non-invasive means for medical sterilisation, the name "Peter MacCallum Clinic" was considered less threatening because the clinic could be positioned as a specialist radiotherapeutic centre rather than it being thought of as a dedicated cancer hospital.

[8] Its main facility was based at the corner William and Little Lonsdale streets, near Flagstaff Gardens where the County Court of Victoria buildings were later built.

In June 2016, the institute moved to the purpose-built building at the entrance to Melbourne's Parkville bio-medical precinct,[8] located at 305 Grattan Street, Melbourne, with satellite services at the Bendigo Base Hospital, Epworth Eastern, the Monash Medical Centre (Moorabbin campus in East Bentleigh) and Sunshine Hospital in St Albans.

[14] The $1 billion cancer treatment and research centre was designed by architects from Silver Thomas Hanley, DesignInc and McBride Charles Ryan.