Electrospray ionization: “We taught elephants to fly”

Electrospray ionization (ESI), for which John Fenn was awarded a share of the 2002 Nobel Prize in chemistry, has revolutionized the use of mass spectrometry for biological and clinical applications. Developed in the late 1980s, building on the pioneering experiments by Malcom Dole’s lab, John Fenn et al. demonstrated the use of ESI for the ‘soft ionization’ of biologically important ‘molecular elephants’, allowing high molecular weight biopolymers (i.e., proteins) to be analysed by mass spectrometry. Here we describe the principles and mechanisms of ESI. Using the field of proteomics, we provide illustrations of how ESI has underpinned discoveries in this field for decades and is enabling emerging methods even today.