Comparative molecular approaches used DNA sequencing and less costly alternatives. Today new DNA sequencing methods are dramatically impacting comparative genomics studies and many old approaches are being adapted or enhanced by the ultra‐high‐throughput sequencing (UHTPS) methods. Even so, the expenses of the newer methods limits their access, while the older methods continue to be improved and applied widely. This article reviews comparative genomics approaches used today but does not review UHTPS methods. A subsequent article by us (Smith and Oh, in preparation) will focus on the impact of the new UHTPS methods on comparative genomics.