Since 1992, Professor McCombie has been with the CSHL and moved into the Genome Center as it opened. Earlier, he worked on establishing a "pome genome project" with David Beach and Tom Marr on the first floor of the remodeled McClintock laboratory.

As reported in the 2014 CSHL Annual Report, his laboratory at the Woodbury site introduced and optimized novel methods of high-throughput genome sequencing. They have brought online a new generation of Illumina sequencers and optimized their function to a level at which 8 to 10 trillion DNA bases can be sequenced in a month.