He worked as a Fellow at Oxford University from 1960 to 1965 and as a Fulbright Scholar at Stanford University in 1963–64. He was appointed Lecturer in Microbiology at the University of Sheffield from 1965 to 1968, Senior Lecturer and Reader from 1968 to 1981 and has been Professor of Microbiology at Sheffield since 1981.
Guest is known for his work on the application of mutant and genetic approaches to define the biochemistry and genetic make-up of central anabolic and catabolic pathways of bacteria, in particular the citric acid cycle and related functions in both aerobic and anaerobic metabolism.