His research interests lie in the synthesis of biologically-active natural products (spanning therapeutic materials to new biotechnological probes) and optoelectronic polymers (with applications to electroluminescent flexible displays and organic solar cells).

[5] Holmes' early work at Cambridge expanded his interest in new techniques for synthesising small molecules that are biologically-active and practically-useful, including natural products (such as alkaloids) and peptidomimetics.

A subsequent collaboration with physicist Richard Friend and co-workers at Cambridge's Cavendish Laboratory revealed the potential of these conjugated polymers for applications such as organic LEDs and rollable displays.

[11] Holmes has served on the editorial or advisory boards of numerous learned scientific journals, including Organic Letters, Chemical Communications and Angewandte Chemie.

[15] In 2004 he was appointed a Member of the Order of Australia "for service to science through research and development, particularly in the fields of organic synthesis and polymer chemistry";[16] and in 2017 was appointed Companion of the Order of Australia for eminent service to science through developments in the field of organic and polymer chemistry as a researcher, editor and academic, and through the governance of nationally recognised, leading scientific organisations.