Plants being sessile organisms are well equipped genomically to respond to environmental stressors peculiar to their habitat. Evolution of plants onto land was enabled by the ability to tolerate extreme water loss (desiccation), a feature that has been retained within genomes but not universally expressed in most land plants today. In the majority of higher plants, desiccation tolerance (DT) is expressed only in reproductive tissues (seeds and pollen), but some 135 angiosperms display vegetative DT. Here, we review genome-level responses associated with DT, pointing out common and yet sometimes discrepant features, the latter relating to evolutionary adaptations to particular niches. Understanding DT can lead to the ultimate production of crops with greater tolerance of drought than is currently realized.