In 2008, it became the country's first medical research institute to target diabetes, heart disease, obesity and their complications at the basic, clinical and population health levels.

Mackeddie persuaded his friend, the photography industry pioneer and philanthropist Thomas Baker and his wife, Alice and sister-in-law, Eleanor Shaw, to assume financial responsibility.

[22] Dr. William J. Penfold, who was internationally renowned in bacteriology and preventative medicine and was prominent in establishing the Australian Medical Research Council,[23] was the first director of the Baker from 1926 until 1938.

Research included the further development of cardiovascular surgery; new techniques of ECG and phonocardiography; treatment of congestive cardiac failure and of arterial hypertension.

[20]: 101 [20]: 119–126 Professor Paul Korner AO, a cardiac physiologist noted for his contributions to the understanding of hypertension, took on the role of director in 1975[20]: 86  and by this time, the sole focus of the institute was cardiovascular disease research.

[33]: 151–157  Notable investigators included Paul Nestel (nutrition, CVD, atherosclerosis and lipid metabolism), Murray Esler (causes and treatment of high blood pressure and heart failure, and effects of stress on the cardiovascular system) and Garry Jennings (causes, prevention and treatment of CVD, and relationship between exercise, blood pressure, sympathetic nervous system activity and glucose metabolism).

Professor John Funder AC was appointed Director in 1990 and bought his work on cardiovascular endocrinology, especially aldosterone action to the institute.

Professor Thomas Marwick FACC FESC FRCP FRACP had been Director of the Menzies Institute for Medical Research at the University of Tasmania and a Cardiologist at the Royal Hobart Hospital.

In May 2023, the Baker Institute appointed respected cardiovascular researcher and cardiologist Professor John Greenwood MBChB, PhD as their new Director.

J. F. Mackeddie, a pathologist originally from Scotland, but who practised in Melbourne in the early 20th century, became a close friend of Thomas Baker through being neighbours on land south of the city.

[21]: 66  Other projects in the early days involved bacteriology, at the time the institute was started, the advancing edge of scientific medicine, and its application to the management of infectious disease in man.

Cardiology research included: The International Diabetes Institute was started in Melbourne in 1984 by Professor Paul Zimmet AO a number of years after his appointment to the Royal Southern Memorial Hospital.

[34] "The research of Paul and his team in Pacific and Indian Ocean populations has provided new insights into the genetic contribution of NIDDM as well as the role of obesity, physical activity, nutrition and sociocultural change in the aetiology of this disorder".

[38] In 1980 Zimmet was asked by the Council of the Australian Diabetes Society to prepare a submission, along with colleague Dr Ian Martin, titled 'Diabetes in Australia'.

[26]: 75  At the same time, with Drv Matthew Cohen, Zimmet was the first to report their experience with home glucose monitoring and its acceptance in the diabetic population.

In 2000 it was the first national study to provide estimates of the number of people with diabetes (based on blood tests) and its public health and societal impact.

The diabetes clinics are the largest in Victoria, with more than 8000 patients per year and continue to be operated by Baker IDI from the organisation's site in Prahran in Melbourne's inner south-east.

The Baker Heart Research Institute is funded from a diverse range of Government and private sources including the corporate sector, trusts and foundations and individual donors.

Financial supporters from the pharmaceutical industry since 2016 include Abbott Laboratories, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly and Company, GlaxoSmithKline, Merck & Co., Novo Nordisk, Pfizer and Sanofi.

One of the significant developments of this partnership has been the Alfred Baker Medical Unit, which was established in 1949 and is the hub of joint research and clinical activity between the two institutions.