The foundation of the MIA is entrenched in the long history of the Sydney Melanoma Unit (SMU). The SMU was established in the early 1960’s after Dr Gerald Milton, then a senior lecturer in the Department of Surgery at the University of Sydney, recognised a particular need to establish a high-class treatment facility for melanoma patients (then known as melanoblastoma). The development of this clinic came following a landmark paper published by the Medical Journal of Australia in 1957 which reported a higher incidence of melanoma in Australia than anywhere else in the world.

In 1966, Dr Milton set up the first Australian Melanoma Clinic at Sydney Hospital and began the first prospective collection of information from patients with a written proforma designed by himself and Dr Cecil Lewis, who was Professor of Surgery in Perth, Western Australia. As patient referrals to the Clinic increased, it became necessary to offer chemotherapy and provide palliative care. The first domiciliary nursing service for patients with advanced melanoma receiving treatment with chemotherapy, immunotherapy or radiotherapy was established.

Professor William McCarthy, a surgeon who had been trained in medical education in the United States, joined the Clinic in 1968. In addition to his clinical activities, he involved the Clinic in community education programs (particularly in the fields of prevention and early diagnosis) and organised fundraising activities to support the Unit's research and educational activities.

In 1972, the Clinic joined the WHO Melanoma Group and began to take part in international clinical trials. As patient numbers increased exponentially, it became clear that computerisation would be necessary to handle the vast amount of clinical, histopathological and epidemiological data that was accumulating. This was achieved in 1972 with the initial intention that the Clinic's database should be primarily a research tool, whilst at the same time providing in-depth information on each patient’s treatment.

About this time, Dr Vincent McGovern of the Royal Prince Alfred Hospital in Sydney, who was an internationally recognised authority on the histopathology of melanoma, developed a close association with the Clinic by virtue of this interest. Following Dr McGovern's tragic death, Professor Stan McCarthy progressively developed the Unit's reputation for internationally pre-eminent melanocytic histopathology. He has awarded an officer of the Order of Australia (AO) in 1996 for his work on melanoma and cancer pathology.

In 1983, the Clinic was transferred from Sydney Hospital to the Royal Prince Alfred Hospital.The Clinic became known as the Sydney Melanoma Unit and was part of the Faculty of Medicine at the University of Sydney. The move to a larger hospital enabled services provided by the Unit to be expanded. One notable development was the nation's first isolated limb perfusion service, set up by Professor John Thompson.

Professor Thompson was, at the time, an academic surgeon at the Royal Prince Alfred Hospital with training not only in surgical oncology but also vascular surgery and transplantation. Since 1993, Professor Thompson has led the Clinic as the major contributor to the international Multicenter Selective Lymphadenectomy Trial. During this time, Professor W.H.McCarthy established the Melanoma Foundation within the University of Sydney, which soon began to generate funds that enabled the Unit to progress much more rapidly with its research and education programs. In 1990, following the retirement of Dr Milton, Professor McCarthy became the Executive Director of the SMU, until he was succeeded by Professor Thompson in 1998.

In 2005 an unprecedented donation to the the Mater Hospital in excess of $40 million, by philanthropist, Mr. Greg Poche, to be used for the construction of a new premises for the Sydney Melanoma Unit, known as The Poche Centre. As a result of this gift the Melanoma Institute Australia was incorporated. Marking a new era for melanoma research, treatment and education the MIA is continuing to build on the work of the SMU with the ultimate aim of finding a cure for melanoma.