Isaac studies the diverse flora of the North American deserts with the goal of understanding the mechanisms underlying diversification and the ecological factors maintaining the resilience of rare plant species. He is currently studying the rock daisies (Perityleae; Asteraceae), a diverse group of arid-adapted plants with a high instance of threatened species in the Death Valley region of Eastern California. His work combines molecular phylogenetics with models of geology and paleoclimate to understand how species have been and are being impacted by global change.