Henry Riggs, then president of Harvey Mudd College, established the institute in 1997 to address what he perceived as a lack of scientists trained to convert new scientific discoveries into practical uses.

[5] David J. Galas, co-founder of the 7th Claremont College, working closely with the visionary President, Henry Riggs, then served as the Chief Academic and Scientific Officer, Dean of the Faculty, Norris Professor of Applied Life Sciences.

[6] The decision to establish Keck Graduate Institute as a seventh Claremont College was met with some opposition, particularly from faculty of the other Claremont Colleges who objected to its lack of tenure, and environmentalists who opposed its plans to build a campus next to the Bernard Field Station, an area of undeveloped scrubland.

The environmental issue was largely settled when KGI decided to establish its campus at a different location, and other opposition gradually faded.

[16] Ionian focuses on molecular diagnostics for emerging and infectious diseases,[17] and in 2004 was awarded a contract to develop a handheld biothreat detector using isothermal amplification of DNA.